Customizable titration for an implantable neurostimulator

ABSTRACT

Systems and methods for customizable titration of an implantable neurostimulator are provided. A method of titrating a neurostimulation signal delivered to a patient from an implantable pulse generator includes delivering a first neurostimulation signal with a first set of parameters, increasing a first value of the first neurostimulation signal at a first rate for a first period of time while delivering the first neurostimulation signal, ceasing delivery of the first neurostimulation signal when the first value reaches a first target value, delivering a second neurostimulation signal with a second set of parameters, and increasing the second neurostimulation signal at a second rate for a second period of time while delivering the second neurostimulation signal.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of and priority to U.S. ProvisionalPatent Application No. 62/558,817, filed Sep. 14, 2017, incorporated byreference herein in its entirety.

BACKGROUND

The present disclosure relates generally to neurostimulation and, morespecifically, to improved systems and methods for managing titration ofstimulation.

Chronic heart failure (CHF) and other forms of chronic cardiacdysfunction (CCD) may be related to an autonomic imbalance of thesympathetic and parasympathetic nervous systems that, if left untreated,can lead to cardiac arrhythmogenesis, progressively worsening cardiacfunction, and eventual patient death. CHF is pathologicallycharacterized by an elevated neuroexitatory state and is accompanied byphysiological indications of impaired arterial and cardiopulmonarybaroreflex function with reduced vagal activity.

CHF triggers compensatory activations of the sympathoadrenal(sympathetic) nervous system and the renin-angiotensin-aldosteronehormonal system, which initially helps to compensate for deterioratingheart-pumping function, yet, over time, can promote progressive leftventricular dysfunction and deleterious cardiac remodeling. Patientssuffering from CHF are at increased risk of tachyarrhythmias, such asatrial fibrillation (AF), ventricular tachyarrhythmias (ventriculartachycardia (VT) and ventricular fibrillation (VF)), and atrial flutter,particularly when the underlying morbidity is a form of coronary arterydisease, cardiomyopathy, mitral valve prolapse, or other valvular heartdisease. Sympathoadrenal activation also significantly increases therisk and severity of tachyarrhythmias due to neuronal action of thesympathetic nerve fibers in, on, or around the heart and through therelease of epinephrine (adrenaline), which can exacerbate analready-elevated heart rate.

The standard of care for managing CCD in general continues to evolve.For instance, new therapeutic approaches that employ electricalstimulation of neural structures that directly address the underlyingcardiac autonomic nervous system imbalance and dysregulation have beenproposed. In one form, controlled stimulation of the cervical vagusnerve beneficially modulates cardiovascular regulatory function. Vagusnerve stimulation (VNS) has been used for the clinical treatment ofdrug-refractory epilepsy and depression, and more recently has beenproposed as a therapeutic treatment of heart conditions such as CHF.

VNS therapy commonly requires implantation of a neurostimulator, asurgical procedure requiring several weeks of recovery before theneurostimulator can be activated and a patient can start receiving VNStherapy. Even after the recovery and activation of the neurostimulator,a full therapeutic dose of VNS is not immediately delivered to thepatient to avoid causing significant patient discomfort and otherundesirable side effects. Instead, to allow the patient to adjust to theVNS therapy, a titration process is utilized in which the intensity isgradually increased over a period of time under a control of aphysician, with the patient given time between successive increases inVNS therapy intensity to adapt to the new intensity. As stimulation ischronically applied at each new intensity level, the patient's tolerancethreshold, or tolerance zone boundary, gradually increases, allowing foran increase in intensity during subsequent titration sessions. Thetitration process can take significantly longer in practice because theincrease in intensity is generally performed by a physician or otherhealthcare provider, and thus, for every step in the titration processto take place, the patient has to visit the provider's office to havethe titration adjustments performed. Scheduling conflicts in theprovider's office may increase the time between titration sessions,thereby extending the overall titration process, during which thepatient in need of VNS does not receive the VNS at the full therapeuticintensity.

For patients receiving VNS therapy for the treatment of epilepsy, atitration process that continues over an extended period of time, suchas six to twelve months, may be somewhat acceptable because thepatient's health condition typically would not worsen in that period oftime. However, for patients being treated for other health conditions,such as CHF, the patient's condition may degrade rapidly if leftuntreated. As a result, there is a much greater urgency to completingthe VNS titration process when treating a patient with a time-sensitivecondition, such as CHF.

Accordingly, a need remains for an approach to efficiently titrateneurostimulation therapy for treating chronic cardiac dysfunction andother conditions while minimizing side effects and related discomfortcaused by the titration or by the VNS therapy itself.

SUMMARY

One embodiment relates to a method of titrating a neurostimulationsignal delivered to a patient from an implantable pulse generator. Themethod includes delivering a first neurostimulation signal with a firstset of parameters, the first set of parameters having a first value forat least one of output current, frequency, pulse width, or duty cycle;increasing the first value of the first neurostimulation signal at afirst rate for a first period of time while delivering the firstneurostimulation signal; and ceasing delivery of the firstneurostimulation signal when the first value reaches a first targetvalue. The method further includes delivering a second neurostimulationsignal with a second set of parameters, the second set of parametershaving a second value for at least one of output current, frequency,pulse width, or duty cycle, the second value being equal to the firsttarget value, and increasing the second neurostimulation signal at asecond rate for a second period of time while delivering the secondneurostimulation signal, the second rate being different than the firstrate.

Another embodiment relates to a neurostimulation system. Theneurostimulation system includes an implantable medical device (IMD)including a neurostimulator coupled to an electrode assembly, theneurostimulator adapted to deliver a neurostimulation signal to apatient. The neurostimulation system also includes a control system. Thecontrol system is programmed to deliver a first neurostimulation signalwith a first set of parameters, the first set of parameters having afirst value for at least one of output current, frequency, pulse width,or duty cycle; increase the first value of the first neurostimulationsignal at a first rate for a first period of time while delivering thefirst neurostimulation signal; and cease delivery of the firstneurostimulation signal when the first value reaches a first targetvalue. The control system is further programmed to deliver a secondneurostimulation signal with a second set of parameters, the second setof parameters having a second value for at least one of output current,frequency, pulse width, or duty cycle, the second value being equal tothe first target value, and increase the second neurostimulation signalat a second rate for a second period of time while delivering the secondneurostimulation signal, the second rate being different than the firstrate.

Another embodiment relates to a non-transitory computer-readable mediumincluding instructions executable by a processor. The instructions areexecutable by the processor to deliver a first neurostimulation signalwith a first set of parameters, the first set of parameters having afirst value for at least one of output current, frequency, pulse width,or duty cycle; increase the first value of the first neurostimulationsignal at a first rate for a first period of time while delivering thefirst neurostimulation signal; and cease delivery of the firstneurostimulation signal when the first value reaches a first targetvalue. The instructions are further executable by the processor todeliver a second neurostimulation signal with a second set ofparameters, the second set of parameters having a second value for atleast one of output current, frequency, pulse width, or duty cycle, thesecond value being equal to the first target value, and increase thesecond neurostimulation signal at a second rate for a second period oftime while delivering the second neurostimulation signal, the secondrate being different than the first rate.

Another embodiment relates to a method of titrating a neurostimulationsignal delivered to a patient from an implantable pulse generator. Themethod includes delivering the neurostimulation signal in conformancewith a first titration aggressiveness profile, the first titrationaggressiveness profile having a first set of parameters having a firstvalue for at least one of output current, frequency, pulse width, orduty cycle; increasing the first value for the at least one of outputcurrent, frequency, pulse width, or duty cycle towards a target value;and receiving a feedback signal from the patient indicating adverseeffects from the neurostimulation signal. The method also includes, inresponse to receiving the feedback signal, modifying theneurostimulation signal to conform with a second titrationaggressiveness profile, the second aggressiveness profile having asecond set of parameters having a second value for at least one ofoutput current, frequency, pulse width, or duty cycle, delivering theneurostimulation signal with the second titration aggressivenessprofile, and increasing the second value for the at least one of outputcurrent, frequency, pulse width, or duty cycle towards the target value.

Another embodiment relates to a neurostimulation system. Theneurostimulation system includes an implantable medical device (IMD)including a neurostimulator coupled to an electrode assembly, theneurostimulator adapted to deliver a neurostimulation signal to apatient. The neurostimulation system also includes a control system. Thecontrol system is programmed to deliver the neurostimulation signal inconformance with a first titration aggressiveness profile, the firsttitration aggressiveness profile having a first set of parameters havinga first value for at least one of output current, frequency, pulsewidth, or duty cycle; increase the first value for the at least one ofoutput current, frequency, pulse width, or duty cycle towards a targetvalue; and receive a feedback signal from the patient indicating adverseeffects from the neurostimulation signal. The control system is alsoprogrammed to, in response to receiving the feedback signal, modify theneurostimulation signal to conform with a second titrationaggressiveness profile, the second aggressiveness profile having asecond set of parameters having a second value for at least one ofoutput current, frequency, pulse width, or duty cycle, deliver theneurostimulation signal with the second titration aggressivenessprofile, and increase the second value for the at least one of outputcurrent, frequency, pulse width, or duty cycle towards the target value.

Another embodiment relates to a non-transitory computer-readable mediumincluding instructions executable by a processor. The instructions areexecutable by the processor to deliver the neurostimulation signal inconformance with a first titration aggressiveness profile, the firsttitration aggressiveness profile having a first set of parameters havinga first value for at least one of output current, frequency, pulsewidth, or duty cycle; increase the first value for the at least one ofoutput current, frequency, pulse width, or duty cycle towards a targetvalue; and receive a feedback signal from the patient indicating adverseeffects from the neurostimulation signal. The instructions are alsoexecutable by the processor to, in response to receiving the feedbacksignal, modify the neurostimulation signal to conform with a secondtitration aggressiveness profile, the second aggressiveness profilehaving a second set of parameters having a second value for at least oneof output current, frequency, pulse width, or duty cycle, deliver theneurostimulation signal with the second titration aggressivenessprofile, and increase the second value for the at least one of outputcurrent, frequency, pulse width, or duty cycle towards the target value.

Another embodiment relates to a programmer configured to communicatewith an implantable pulse generator that provides neurostimulation. Theprogrammer includes communication circuitry, a user interface, aprocessor, and a memory. The memory has instructions stored thereonthat, when executed by the processor, cause the processor to collect,via the communication circuitry, data about ongoing neurostimulationbeing applied by the implantable pulse generator while in communicationwith the communication circuitry and display, via the user interface, anindication relating to a timing of neurostimulation bursts applied bythe implantable pulse generator while in communication with thecommunication circuitry based on the collected data.

Another embodiment relates to a method of displaying, by a programmerconfigured to communicate with an implantable pulse generator, anindication of active neurostimulation applied by the implantable pulsegenerator. The method includes collecting data about ongoingneurostimulation being applied by the implantable pulse generator whilein communication with the programmer and displaying an indicationrelating to a timing of neurostimulation bursts applied by theimplantable pulse generator while in communication with the programmerbased on the collected data.

Another embodiment relates to a non-transitory computer-readable mediumfor a programmer including instructions executable by a processor. Theinstructions are executable by the processor to collect data from animplantable pulse generator about ongoing neurostimulation being appliedby the implantable pulse generator while in communication with theprogrammer and display, via a user interface, an indication relating toa timing of neurostimulation bursts applied by the implantable pulsegenerator while in communication with the programmer based on thecollected data.

Another embodiment relates to a method of titrating a neurostimulationsignal delivered to a patient from an implantable pulse generator. Themethod includes delivering the neurostimulation signal in conformancewith a first set of parameters, the first set of parameters having afirst value for at least one of output current, frequency, pulse width,or duty cycle, and receiving a first indicator, the indicator beingassociated with at least one of a titration hold time or a titrationhold duration. The method also includes initiating a titration hold ofthe titrating of the neurostimulation signal in response to the firstindicator, the titration hold corresponding to the continuation of theneurostimulation signal conforming with the first set of parameters, andreceiving a second indicator, the second indicator associated with atleast one of a titration resumption time or a completion of thetitration hold duration. The method further includes resuming thetitrating of the neurostimulation signal in response to the secondindicator. The titration hold is a temporary hold configured to reduceadverse effects observed by the patient during the titrating.

Another embodiment relates to a neurostimulation system. Theneurostimulation system includes an implantable medical device (IMD)including a neurostimulator coupled to an electrode assembly, theneurostimulator adapted to deliver a neurostimulation signal to apatient. The neurostimulation system also includes a control system. Thecontrol system is programmed to deliver the neurostimulation signal inconformance with a first set of parameters, the first set of parametershaving a first value for at least one of output current, frequency,pulse width, or duty cycle, and receive a first indicator, the indicatorbeing associated with at least one of a titration hold time or atitration hold duration. The control system is also programmed toinitiate a titration hold of the titrating of the neurostimulationsignal in response to the first indicator, the titration holdcorresponding to the continuation of the neurostimulation signalconforming with the first set of parameters, and receive a secondindicator, the second indicator associated with at least one of atitration resumption time or a completion of the titration holdduration. The control system is further programmed to resume thetitrating of the neurostimulation signal in response to the secondindicator. The titration hold is a temporary hold configured to reduceadverse effects observed by the patient during the titrating.

Another embodiment relates to a non-transitory computer-readable mediumincluding instructions executable by a processor. The instructions areexecutable by the processor to deliver the neurostimulation signal inconformance with a first set of parameters, the first set of parametershaving a first value for at least one of output current, frequency,pulse width, or duty cycle, and receive a first indicator, the indicatorbeing associated with at least one of a titration hold time or atitration hold duration. The instructions are also executable by theprocessor to initiate a titration hold of the titrating of theneurostimulation signal in response to the first indicator, thetitration hold corresponding to the continuation of the neurostimulationsignal conforming with the first set of parameters, and receive a secondindicator, the second indicator associated with at least one of atitration resumption time or a completion of the titration holdduration. The instructions are further executable by the processor toresume the titrating of the neurostimulation signal in response to thesecond indicator. The titration hold is a temporary hold configured toreduce adverse effects observed by the patient during the titrating.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features, characteristics, and advantages of the presentdisclosure will become apparent to a person of ordinary skill in the artfrom the following detailed description of embodiments of the presentdisclosure, made with reference to the drawings annexed, in which likereference characters refer to like elements.

FIG. 1 is a front anatomical diagram showing, by way of example,placement of an implantable vagus stimulation device in a male patient,in accordance with one embodiment.

FIGS. 2A and 2B are diagrams respectively showing the implantableneurostimulator and the stimulation therapy lead of FIG. 1, according toan exemplary embodiment.

FIG. 3 is a diagram showing an external programmer for use with theimplantable neurostimulator of FIG. 1, according to an exemplaryembodiment.

FIG. 4 is a diagram showing electrodes provided as on the stimulationtherapy lead of FIG. 2 in place on a vagus nerve in situ, according toan exemplary embodiment.

FIG. 5 is a flowchart of a method for delivering vagus nerve stimulationtherapy, according to an exemplary embodiment.

FIGS. 6A and 6B are flowcharts of a titration process, according to anexemplary embodiment.

FIGS. 7A and 7B are block diagrams of neurostimulation systems,according to an exemplary embodiment.

FIG. 8 is a titration assist management dashboard, according to anexemplary embodiment.

FIG. 9 is a patient titration graph of the titration assist managementdashboard of FIG. 8, according to an exemplary embodiment.

FIG. 10 is a flowchart of a process for managing patients using thetitration assist management dashboard, according to an exemplaryembodiment.

FIG. 11 is a patient titration graph incorporating a titration dwellpoint, according to an exemplary embodiment.

FIG. 12 is a flowchart of a titration process incorporating a titrationdwell point, according to an exemplary embodiment.

FIG. 13 is a patient titration graph illustrating different titrationaggressiveness profiles, according to an exemplary embodiment.

FIG. 14 is a flowchart of a titration process including differenttitration aggressiveness profiles, according to an exemplary embodiment.

FIG. 15 is a flowchart of process of displaying an indication of activeneurostimulation, according to an exemplary embodiment.

FIG. 16 is a patient titration graph incorporating a titration black-outperiod, according to an exemplary embodiment.

FIG. 17 is a flowchart of a titration process incorporating a titrationblack-out period, according to an exemplary embodiment.

DETAILED DESCRIPTION

Various aspects of the disclosure will now be described with regard tocertain examples and embodiments, which are intended to illustrate butnot to limit the disclosure. Nothing in this disclosure is intended toimply that any particular feature or characteristic of the disclosedembodiments is essential. The scope of protection is defined by theclaims that follow this description and not by any particular embodimentdescribed herein. Before turning to the figures, which illustrateexample embodiments in detail, it should be understood that theapplication is not limited to the details or methodology set forth inthe description or illustrated in the figures. It should also beunderstood that the terminology is for the purpose of description onlyand should not be regarded as limiting.

CHF and other cardiovascular diseases cause derangement of autonomiccontrol of the cardiovascular system, favoring increased sympathetic anddecreased parasympathetic central outflow. These changes are accompaniedby elevation of basal heart rate arising from chronic sympathetichyperactivation along the neurocardiac axis.

The vagus nerve is a diverse nerve trunk that contains both sympatheticand parasympathetic fibers and both afferent and efferent fibers. Thesefibers have different diameters and myelination and subsequently havedifferent activation thresholds. This results in a graded response asintensity is increased. Low intensity stimulation results in aprogressively greater tachycardia, which then diminishes and is replacedwith a progressively greater bradycardia response as intensity isfurther increased. Peripheral neurostimulation therapies that target thefluctuations of the autonomic nervous system have been shown to improveclinical outcomes in some patients. Specifically, autonomic regulationtherapy results in simultaneous creation and propagation of efferent andafferent action potentials within nerve fibers comprising the cervicalvagus nerve. The therapy directly improves autonomic balance by engagingboth medullary and cardiovascular reflex control components of theautonomic nervous system. Upon stimulation of the cervical vagus nerve,action potentials propagate away from the stimulation site in twodirections, efferently toward the heart and afferently toward the brain.Efferent action potentials influence the intrinsic cardiac nervoussystem and the heart and other organ systems, while afferent actionpotentials influence central elements of the nervous system.

An implantable vagus nerve stimulator, such as used to treatdrug-refractory epilepsy and depression, can be adapted for use inmanaging chronic cardiac dysfunction (CCD) through therapeuticbi-directional vagus nerve stimulation. FIG. 1 is a front anatomicaldiagram showing, by way of example, placement of an implantable medicaldevice (e.g., a vagus nerve stimulation (VNS) system 11, as shown inFIG. 1) in a male patient 10, according to an exemplary embodiment. TheVNS provided through the stimulation system 11 operates under severalmechanisms of action. These mechanisms include increasingparasympathetic outflow and inhibiting sympathetic effects by inhibitingnorepinephrine release and adrenergic receptor activation. Moreimportantly, VNS triggers the release of the endogenous neurotransmitteracetylcholine and other peptidergic substances into the synaptic cleft,which has several beneficial anti-arrhythmic, anti-apoptotic, andanti-inflammatory effects as well as beneficial effects at the level ofthe central nervous system.

The implantable vagus stimulation system 11 comprises an implantableneurostimulator or pulse generator 12 and a stimulating nerve electrodeassembly 125. The neurostimulator or pulse generator may be a voltagestimulator or, more preferably, a current stimulator. The stimulatingnerve electrode assembly 125, comprising at least an electrode pair, isconductively connected to the distal end of an insulated, electricallyconductive lead assembly 13 and electrodes 14. The electrodes 14 may beprovided in a variety of forms, such as, e.g., helical electrodes, probeelectrodes, cuff electrodes, as well as other types of electrodes.

The implantable vagus stimulation system 11 can be remotely accessedfollowing implant through an external programmer, such as the programmer40 shown in FIG. 3 and described in further detail below. The programmer40 can be used by healthcare professionals to check and program theneurostimulator 12 after implantation in the patient 10 and to adjuststimulation parameters during the stimulation titration process. In someembodiments, an external magnet may provide basic controls. For example,an electromagnetic controller may enable the patient 10 or healthcareprofessional to interact with the implanted neurostimulator 12 toexercise increased control over therapy delivery and suspension. Forfurther example, an external programmer may communicate with theneurostimulation system 11 via other wired or wireless communicationmethods, such as, e.g., wireless RF transmission. Together, theimplantable vagus stimulation system 11 and one or more of the externalcomponents form a VNS therapeutic delivery system.

The neurostimulator 12 is typically implanted in the patient's right orleft pectoral region generally on the same side (ipsilateral) as thevagus nerve 15, 16 to be stimulated, although otherneurostimulator-vagus nerve configurations, including contra-lateral andbi-lateral are possible. A vagus nerve typically comprises two branchesthat extend from the brain stem respectively down the left side andright side of the patient, as seen in FIG. 1. The electrodes 14 aregenerally implanted on the vagus nerve 15, 16 about halfway between theclavicle 19 a-b and the mastoid process. The electrodes may be implantedon either the left or right side. The lead assembly 13 and electrodes 14are implanted by first exposing the carotid sheath and chosen branch ofthe vagus nerve 15, 16 through a latero-cervical incision (perpendicularto the long axis of the spine) on the ipsilateral side of the patient'sneck 18. The helical electrodes 14 are then placed onto the exposednerve sheath and tethered. A subcutaneous tunnel is formed between therespective implantation sites of the neurostimulator 12 and helicalelectrodes 14, through which the lead assembly 13 is guided to theneurostimulator 12 and securely connected. Additionally, in variousembodiments, the neurostimulator 12 connects to the electrodes 14 asshown in FIG. 4 (e.g., at the top helices).

In one embodiment, the neural stimulation is provided as a low levelmaintenance dose independent of cardiac cycle. The stimulation system 11bi-directionally stimulates either the left vagus nerve 15 or the rightvagus nerve 16. However, it is contemplated that multiple electrodes 14and multiple leads 13 could be utilized to stimulate simultaneously,alternatively, or in other various combinations. Stimulation may bethrough multimodal application of continuously-cycling, intermittent andperiodic electrical stimuli, which are parametrically defined throughstored stimulation parameters and timing cycles. Both sympathetic andparasympathetic nerve fibers in the vagosympathetic complex arestimulated. Generally, cervical vagus nerve stimulation results inpropagation of action potentials from the site of stimulation in abi-directional manner. The application of bi-directional propagation inboth afferent and efferent directions of action potentials withinneuronal fibers comprising the cervical vagus nerve improves cardiacautonomic balance. Afferent action potentials propagate toward theparasympathetic nervous system's origin in the medulla in the nucleusambiguus, nucleus tractus solitarius, and the dorsal motor nucleus, aswell as towards the sympathetic nervous system's origin in theintermediolateral cell column of the spinal cord. Efferent actionpotentials propagate toward the heart 17 to activate the components ofthe heart's intrinsic nervous system. Either the left or right vagusnerve 15, 16 can be stimulated by the stimulation system 11. The rightvagus nerve 16 has a moderately lower (approximately 30%) stimulationthreshold than the left vagus nerve 15 for heart rate effects at thesame stimulation frequency and pulse width.

The VNS therapy is delivered autonomously to the patient's vagus nerve15, 16 through three implanted components that include a neurostimulator12, lead assembly 13, and electrodes 14. FIGS. 2A and 2B are diagramsrespectively showing the implantable neurostimulator 12 and thestimulation lead assembly 13 of FIG. 1. In one embodiment, theneurostimulator 12 can be adapted from a VNS Therapy Demipulse Model 103or AspireSR Model 106 pulse generator, manufactured and sold byCyberonics, Inc., Houston, Tex., although other manufactures and typesof implantable VNS neurostimulators could also be used. The stimulationlead assembly 13 and electrodes 14 are generally fabricated as acombined assembly and can be adapted from a Model 302 lead, PerenniaDURAModel 303 lead, or PerenniaFLEX Model 304 lead, also manufactured andsold by Cyberonics, Inc., in three sizes based, for example, on ahelical electrode inner diameter, although other manufactures and typesof single-pin receptacle-compatible therapy leads and electrodes couldalso be used.

Referring first to FIG. 2A, the system 20 may be configured to providemultimodal vagus nerve stimulation. In a maintenance mode, theneurostimulator 12 is parametrically programmed to delivercontinuously-cycling, intermittent and periodic ON-OFF cycles of VNS.Such delivery produces action potentials in the underlying nerves thatpropagate bi-directionally, both afferently and efferently.

The neurostimulator 12 includes an electrical pulse generator that istuned to improve autonomic regulatory function by triggering actionpotentials that propagate both afferently and efferently within thevagus nerve 15, 16. The neurostimulator 12 is enclosed in a hermeticallysealed housing 21 constructed of a biocompatible material, such astitanium. The housing 21 contains electronic circuitry 22 powered by abattery 23, such as a lithium carbon monofluoride primary battery or arechargeable secondary cell battery. The electronic circuitry 22 may beimplemented using complementary metal oxide semiconductor integratedcircuits that include a microprocessor controller that executes acontrol program according to stored stimulation parameters and timingcycles; a voltage regulator that regulates system power; logic andcontrol circuitry, including a recordable memory 29 within which thestimulation parameters are stored, that controls overall pulse generatorfunction, receives and implements programming commands from the externalprogrammer, or other external source, collects and stores telemetryinformation, processes sensory input, and controls scheduled andsensory-based therapy outputs; a transceiver that remotely communicateswith the external programmer using radio frequency signals; an antenna,which receives programming instructions and transmits the telemetryinformation to the external programmer; and a reed switch 30 thatprovides remote access to the operation of the neurostimulator 12 usingan external programmer, a simple patient magnet, or an electromagneticcontroller. The recordable memory 29 can include both volatile (dynamic)and non-volatile/persistent (static) forms of memory, within which thestimulation parameters and timing cycles can be stored. Other electroniccircuitry and components are possible.

The neurostimulator 12 includes a header 24 to securely receive andconnect to the lead assembly 13. In one embodiment, the header 24encloses a receptacle 25 into which a single pin for the lead assembly13 can be received, although two or more receptacles could also beprovided, along with the corresponding electronic circuitry 22. Theheader 24 may internally include a lead connector block (not shown), asetscrew, and a spring contact (not shown) that electrically connects tothe lead ring, thus completing an electrical circuit.

In some embodiments, the housing 21 may also contain a heart rate sensor31 that is electrically interfaced with the logic and control circuitry,which receives the patient's sensed heart rate as sensory inputs. Theheart rate sensor 31 monitors heart rate using an ECG-type electrode.Through the electrode, the patient's heartbeat can be sensed bydetecting ventricular depolarization. In a further embodiment, aplurality of electrodes can be used to sense voltage differentialsbetween electrode pairs, which can undergo signal processing for cardiacphysiological measures, for instance, detection of the P-wave, QRScomplex, and T-wave. The heart rate sensor 31 provides the sensed heartrate to the control and logic circuitry as sensory inputs that can beused to determine the onset or presence of arrhythmias, particularly VT,and/or to monitor and record changes in the patient's heart rate overtime or in response to applied stimulation signals.

Referring next to FIG. 2B, the lead assembly 13 delivers an electricalsignal from the neurostimulator 12 to the vagus nerve 15, 16 via theelectrodes 14. On a proximal end, the lead assembly 13 has a leadconnector 27 that transitions an insulated electrical lead body to ametal connector pin 28 with a metal connector ring. During implantation,the connector pin 28 is guided through the receptacle 25 into the header24 and securely fastened in place using the setscrew (not shown) toelectrically couple one electrode of the lead assembly 13 to theneurostimulator 12 while a spring contact (not shown) makes electricalcontact to the ring connected to the other electrode. On a distal end,the lead assembly 13 terminates with the electrode 14, which bifurcatesinto a pair of anodic and cathodic electrodes 62 (as further describedinfra with reference to FIG. 4). In one embodiment, the lead connector27 is manufactured using silicone, and the connector pin 28 and ring aremade of stainless steel, although other suitable materials could beused, as well. The insulated lead body of the lead assembly 13 utilizesa silicone-insulated alloy conductor material.

In some embodiments, the electrodes 14 are helical and placed around thecervical vagus nerve 15, 16 at the location below where the superior andinferior cardiac branches separate from the cervical vagus nerve. Inalternative embodiments, the helical electrodes may be placed at alocation above where one or both of the superior and inferior cardiacbranches separate from the cervical vagus nerve. In one embodiment, thehelical electrodes 14 are positioned around the patient's vagus nerveoriented with the end of the helical electrodes 14 facing the patient'shead. In an alternate embodiment, the helical electrodes 14 arepositioned around the patient's vagus nerve 15, 16 oriented with the endof the helical electrodes 14 facing the patient's heart 17. At thedistal end, the insulated electrical lead body of the lead assembly 13is bifurcated into a pair of lead bodies that are connected to a pair ofelectrodes. The polarity of the electrodes could be configured into aproximal anode and a distal cathode, or a proximal cathode and a distalanode.

The neurostimulator 12 may be interrogated prior to implantation andthroughout the therapeutic period with a healthcare provider-operablecontrol system comprising an external programmer and programming wand(shown in FIG. 3) for checking proper operation, downloading recordeddata, diagnosing problems, and programming operational parameters. FIG.3 is a diagram showing an external programmer 40 for use with theimplantable neurostimulator 12 of FIG. 1. The external programmer 40includes a healthcare provider operable programming computer 41 and aprogramming wand 42. Generally, use of the external programmer isrestricted to healthcare providers, while more limited manual control isprovided to the patient through “magnet mode.”

In one embodiment, the external programmer 40 executes applicationsoftware 45 specifically designed to interrogate the neurostimulator 12.The programming computer 41 interfaces to the programming wand 42through a wired or wireless data connection. The programming wand 42 canbe adapted from a Model 201 Programming Wand, manufactured and sold byCyberonics, Inc., and the application software 45 can be adapted fromthe Model 250 Programming Software suite, licensed by Cyberonics, Inc.Other configurations and combinations of external programmer 40,programming wand 42, and application software 45 are possible.

The programming computer 41 can be implemented using a general purposeprogrammable computer and can be a personal computer, laptop computer,ultrabook computer, netbook computer, handheld computer, tabletcomputer, smart phone, or other form of computational device. Forexample, in one embodiment, the programming computer 41 is a tabletprogrammer with a wired or wireless data connection to the programmingwand 42. The programming computer 41 functions through those componentsconventionally found in such devices, including, for instance, a centralprocessing unit, volatile and persistent memory, touch-sensitivedisplay, control buttons, peripheral input and output ports, and networkinterface. The computer 41 operates under the control of the applicationsoftware 45, which is executed as program code as a series of process ormethod modules or steps by the programmed computer hardware. Otherassemblages or configurations of computer hardware, firmware, andsoftware are possible.

Operationally, the programming computer 41, when connected to aneurostimulator 12 through wireless telemetry using the programming wand42, can be used by a healthcare provider to remotely interrogate theneurostimulator 12 and modify stored stimulation parameters. Theprogramming wand 42 provides data conversion between the digital dataaccepted by and output from the programming computer and the radiofrequency signal format that is required for communication with theneurostimulator 12. In other embodiments, the programming computer maycommunicate with the implanted neurostimulator 12 using other wirelesscommunication methods, such as wireless RF transmission. The programmingcomputer 41 may further be configured to receive inputs, such asphysiological signals received from patient sensors (e.g., implanted orexternal). These sensors may be configured to monitor one or morephysiological signals, e.g., vital signs, such as body temperature,pulse rate, respiration rate, blood pressure, etc. These sensors may becoupled directly to the programming computer 41 or may be coupled toanother instrument or computing device which receives the sensor inputand transmits the input to the programming computer 41. The programmingcomputer 41 may monitor, record, and/or respond to the physiologicalsignals in order to effectuate stimulation delivery in accordance withsome embodiments.

The healthcare provider operates the programming computer 41 through auser interface that includes a set of input controls 43 (e.g., includinga touchscreen of the programming computer 41) and a visual display 44,which could be touch-sensitive, upon which to monitor progress, viewdownloaded telemetry and recorded physiology, and review and modifyprogrammable stimulation parameters. The telemetry can include reportson device history that provide patient identifier, implant date, modelnumber, serial number, magnet activations, total ON time, totaloperating time, manufacturing date, and device settings and stimulationstatistics, and on device diagnostics that include patient identifier,model identifier, serial number, firmware build number, implant date,communication status, output current status, measured current delivered,lead impedance, and battery status. Other kinds of telemetry ortelemetry reports are possible.

During interrogation, the programming wand 42 is held by its handle 46and the bottom surface 47 of the programming wand 42 is placed on thepatient's chest over the location of the implanted neurostimulator 12. Aset of indicator lights 49 can assist with proper positioning of thewand and a set of input controls 48 enable the programming wand 42 to beoperated directly, rather than requiring the healthcare provider toawkwardly coordinate physical wand manipulation with control inputs viathe programming computer 41. The sending of programming instructions andreceipt of telemetry information occur wirelessly through radiofrequency signal interfacing. Other programming computer and programmingwand operations are possible.

FIG. 4 is a diagram showing the helical electrodes 14 provided as on thestimulation lead assembly 13 of FIG. 2 in place on a vagus nerve 15, 16in situ 50. Although described with reference to a specific manner andorientation of implantation, the specific surgical approach andimplantation site selection particulars may vary, depending uponphysician discretion and patient physical structure.

Under one embodiment, helical electrodes 14 may be positioned on thepatient's vagus nerve 61 oriented with the end of the helical electrodes14 facing the patient's head. At the distal end, the insulatedelectrical lead body of the lead assembly 13 is bifurcated into a pairof lead bodies 57, 58 that are connected to a pair of electrodes 51, 52.The polarity of the electrodes 51, 52 could be configured into aproximal anode and a distal cathode, or a proximal cathode and a distalanode. In addition, an anchor tether 53 is fastened over or inconnection with the lead bodies 57, 58 that maintains the helicalelectrodes' position on the vagus nerve 61 following implant. In oneembodiment, the conductors of the electrodes 51, 52 are manufacturedusing a platinum and iridium alloy, while the helical materials of theelectrodes 51, 52 and the anchor tether 53 are a silicone elastomer.

During surgery, the electrodes 51, 52 and the anchor tether 53 arecoiled around the vagus nerve 61 proximal to the patient's head, eachwith the assistance of a pair of sutures 54, 55, 56, made of polyesteror other suitable material, which help the surgeon to spread apart therespective helices. The lead bodies 57, 58 of the electrodes 51, 52 areoriented distal to the patient's head and aligned parallel to each otherand to the vagus nerve 61. A strain relief bend 60 can be formed on thedistal end with the insulated electrical lead body of the lead assembly13 aligned, for example, parallel to the helical electrodes 14 andattached to the adjacent fascia by a plurality of tie-downs 59 a-b.

The neurostimulator 12 delivers VNS under control of the electroniccircuitry 22. The stored stimulation parameters are programmable. Eachstimulation parameter can be independently programmed to define thecharacteristics of the cycles of therapeutic stimulation and inhibitionto ensure optimal stimulation for a patient 10. The programmablestimulation parameters include output current, signal frequency, pulsewidth, signal ON time, signal OFF time, magnet activation (for VNSspecifically triggered by “magnet mode”), and reset parameters. Otherprogrammable parameters are possible. In addition, sets or “profiles” ofpreselected stimulation parameters can be provided to physicians withthe external programmer and fine-tuned to a patient's physiologicalrequirements prior to being programmed into the neurostimulator 12.

Therapeutically, the VNS may be delivered as a multimodal set oftherapeutic doses, which are system output behaviors that arepre-specified within the neurostimulator 12 through the storedstimulation parameters and timing cycles implemented in firmware andexecuted by the microprocessor controller. The therapeutic doses includea maintenance dose that includes continuously-cycling, intermittent andperiodic cycles of electrical stimulation during periods in which thepulse amplitude is greater than 0 mA (“therapy ON”) and during periodsin which the pulse amplitude is 0 mA (“therapy OFF”).

The neurostimulator 12 can operate either with or without an integratedheart rate sensor. Additionally, where an integrated leadless heart ratemonitor is available, the neurostimulator 12 can provide autonomiccardiovascular drive evaluation and self-controlled titration. Finally,the neurostimulator 12 can be used to counter natural circadiansympathetic surge upon awakening and manage the risk of cardiacarrhythmias during or attendant to sleep, particularly sleep apneicepisodes.

Several classes of implantable medical devices provide therapy usingelectrical current as a stimulation vehicle. When such a systemstimulates certain organs or body structures like the vagus nerve,therapeutic levels of electrical stimulation are usually not welltolerated by patients without undergoing a process known as titration.Titration is a systematic method or process of incrementally increasingthe stimulation parameters employed by an implanted device to deliver astimulation current to the patient at increasing levels that achieve orimprove therapeutic benefit while minimizing side effects that coulddisrupt the stimulation therapy. Titration in a neuromodulation systemmay be necessary due to centrally-mediated side effects elicited bylarge changes in stimulation intensity. For example, the neuromodulationsystem may be unable to instantly change the intensity of deliveredneurostimulation from an inactive state (e.g., stimulation programmed toOFF) to full therapeutic intensity without the patient experiencingadverse effects (e.g., triggering an expiratory cough reflex). Thatbeing said, the central processing areas of vagal afferents recruited atlow stimulation intensity can often handle small stimulation intensityincreases over periods of time without effect. As such, titrationusually involves bringing the patient to an initial stimulation levelthat is tolerable to the patient (i.e., below an initial tolerancethreshold), waiting for a period of time for the patient to adjust tothe continuing delivery of the initial stimulation level and to define ahigher tolerance threshold of the patient, and then increasing theinitial stimulation level to a higher stimulation level that is, in somepatients, greater than the initial tolerance threshold, and so on. Thisprocess is repeated in sequences that progress from a stimulationdelivery provided over a waiting period, and then to an increase in astimulation level that defines the next sequence of the stimulationdelivery and the next waiting period. The central neural processorsgradually remodel and accommodate the increasing stimulation intensityif given sufficient time between increasing stimulation steps (e.g.,function without adverse effects such as triggering the cough reflex).

FIG. 5 is a flow diagram showing a method for delivering vagus nervestimulation therapy, according to an exemplary embodiment. A titrationprocess 400 is used to gradually increase the stimulation intensity to adesired therapeutic level or maintenance dosage level. If thestimulation intensity is increased too quickly before the patient isfully accommodated to the stimulation signal, the patient may experienceundesirable side effects, such as coughing, hoarseness, throatirritation, or expiratory reflex. The titration process graduallyincreases stimulation intensity within a tolerable level and maintainsthat intensity for a period of time to permit the patient to adjust toeach increase in intensity, thereby gradually increasing the patient'sside effect tolerance zone boundary to so as to accommodate subsequentincreases in intensity. The titration process continues until adequateadaptation is achieved. In embodiments, the titration process isautomated and is executed by the implanted device without manualadjustment of the stimulation intensity by the subject or health careprovider. As will be described in greater detail below, adequateadaptation is a composite threshold comprising one or more of thefollowing: an acceptable side effect level, a target intensity level,and a target physiological response. In some embodiments, adequateadaption includes all three objectives: an acceptable side effect level,a target intensity level, and a target physiological response.

In some embodiments, the titration process is a mix of automation andphysician input. As will be described in greater detail below, aphysician may use intermediate holds to stop the automated titration atcertain thresholds (e.g., a certain number of days or weeks, certainstimulation parameter values, etc.) and evaluate the patient beforeresuming the automated titration. The physician may receive a graphicaltitration history to review how the automated titration process has beenprogressing from one sequence to the next. The graphical titrationhistory may include markers. The markers may represent intermediateholds, when target parameters are reached between adjacent sequences,etc. After the physician has resumed the automatic titration, the nextsequence of automated titration may progress until the next intermediatehold is reached.

As described above, it may be desirable to minimize the amount of timerequired to complete the titration process so as to begin delivery ofthe stimulation at therapeutically desirable levels, particularly whenthe patient is being treated for an urgent condition such as CHF. Inaddition, it is desirable to utilize a maintenance dose intensity at theminimum level required to achieve the desired therapeutic effect. Thiscan reduce power requirements for the neurostimulator and reduce patientdiscomfort.

It has been observed that a patient's side effect profile is moresensitive to the stimulation output current than to the otherstimulation parameters, such as frequency, pulse width, and duty cycle.As a result, accommodation to the stimulation output current is aprimary factor in completing the titration process. It has also beenobserved that if the other stimulation parameters are maintained at alevel below the target levels, the output current can be increased tohigher levels without eliciting undesirable side effects that would beresult when the other parameters are at the target level. As a result,increasing the target output current while maintaining the otherstimulation parameters (pulse width in particular) at reduced levels canresult in a faster accommodation and shorter overall titration time thanwould be achieved by attempting to increase the output current whilestimulating at the target pulse width.

Referring again to FIG. 5, in step 401, a stimulation system 11,including a neurostimulator 12, a nerve stimulation lead assembly 13,and a pair of electrodes 14, is implanted in the patient. In step 402,the patient undergoes an optional post-surgery recovery period, duringwhich time the surgical incisions are allowed to heal and no VNS therapyoccurs. This period may last, e.g., two weeks post-surgery. In step 403,the stimulation therapy is initiated with the initiation of a titrationprocess. During this titration process, VNS therapy is titrated byadjusting one or more of the stimulation parameters, including outputcurrent, pulse width, signal frequency, and duty cycle, as will bedescribed in greater detail below. Completion of the titration processdetermines the stimulation intensity to be used for subsequentmaintenance doses delivered in step 404. These maintenance doses may beselected to provide the minimum stimulation intensity necessary toprovide the desired therapeutic result.

FIG. 6A is a flow diagram illustrating a titration process 500,according to an exemplary embodiment. Process 500 includes settingtitration parameters (step 501), initiating titration (step 502),stopping titration at an intermediate hold (step 503), and resumingtitration (step 504).

In step 501, a physician sets the titration parameters via programmer40, which are received by the implantable vagus nerve stimulation system11. In some embodiments, the titration parameters may be defined by oneor more titration algorithms that may be selected by the physician, ormay be presented to the physician as a preferred or recommended list oftitration parameters that the programming physician can adopt. In otherembodiments, rather than present the physician with a set titrationalgorithm with fixed algorithm values, the physician may be presentedwith default values that could be manually adjusted. The titrationparameter starting values, target values, and/or increment values foramplitude, pulse width, frequency, and/or duty cycle may be adjustable,as may the time interval between titration steps. Time of day and delayto therapy start may also be programmable as a titration parameter. Thetitration parameters may also include one or more intermediate holdsthat maintain certain parameters until the physician indicates that theautomated titration can continue. The physician may be limited so thatmodification can be made to only a select group of parameters, or someparameters may be considered to be in a locked state until unlocked bythe physician. In some embodiments, the physician is able to modify alarge number of titration parameters (e.g., 10-12 parameters).

Alternatively, rather than give the physician control over the titrationparameter values themselves, the physician's options for the titrationprocess may be presented as a set of “aggressiveness” options to selectfrom, each of which would be used by the system to determine the valuesto use. For example, the physician may be able to choose from anaggressive profile, a moderate profile, or a light profile (sensitive)that is appropriate for certain types of patients that do not requiredetailed titration parameter programming. More or fewer aggressivenessprofiles could be used, and the aggressiveness profiles may correspondto the overall health status of the patient, the patient's sensitivityto stimulation therapies or titration processes, or the patient'smedical history. The aggressiveness profile selected by the physicianmay result in a predetermined set of titration parameters beingselected. The predetermined titration parameters may vary betweendifferent aggressiveness profiles, and some titration parameters mayremain constant, or similar, between various aggressiveness profiles.For example, the aggressive profile may be suitable for patients thathave a high toleration for the titration process and may include shortertime intervals between titration steps, higher intensity target values,and/or larger increment values (e.g., as compared to the moderate orlight profiles) that may result in an achievement of a suitable therapylevel more quickly as compared to the moderate or light profiles. Whilesome of the parameters may promote a more aggressive titrationprogression, some of the parameters may be consistent with parameters ofother profiles (e.g., titration holds).

In some embodiments, each of the aggressiveness profiles may be mappedby the system to a set of parameters or a range of parameters. Forexample, if the user selects the aggressive profile, the system mayreceive the user selection and set the values of one or more parameters(e.g., amplitude, pulse width, frequency, duty cycle, intervals betweentitration steps, and/or other parameters) to a first set of values. Ifthe user selects the moderate profile, the system may set the values ofthe parameters to a second predetermined set or range of values that isdifferent than the set associated with the aggressive profile. In someembodiments, the physicians are limited to modification of theparameters within a range of boundary values. The ranges may be for thedefault parameters, or may be set individually for the aggressivenessoptions (e.g., the ranges for the aggressive profile and the moderateprofile may be different, but may overlap for some parameters). Thephysician may be able to customize the parameters in the presetprofiles. Titrating according to aggressiveness profiles is described infurther detail below with respect to FIGS. 13 and 14. In step 502, thephysician initiates titration using the titration parameters defined at501.

In step 503, titration is stopped at a titration hold. The titrationhold may be an intermediate hold set by the physician during step 501.The VNS system 11 may perform automated titration according to process600, described below. However, the physician is given the option(through the programmer 40) to designate intermediate points at whichthe titration algorithm would pause and await manual (programmer-based)activation by the physician. These hold points may be either time based(e.g. after 2, 4, 6, and/or 8 weeks of titration) or stimulation based(e.g. once stimulation amplitude reaches 1.0, 1.5, 2.0, and/or 2.5 mA).This would allow the physician to evaluate the patient in the clinicbefore deciding to continue titration. The physician releases the holdon the titration with the programmer 40 once the patient has beenevaluated. The physician may also modify parameters during the clinicalevaluations.

The holds may be predefined for the entire titration process duringinitial set up. Alternatively, the physician may have the option ofsetting a new intermediate hold when evaluating the patient. Theintermediate holds may be consistent throughout the titration process(e.g., every 2 weeks, every 0.5 mA, etc.). In another embodiment, theintermediate holds are different for at least one hold (e.g., 4 weeks tothe first hold, 2 weeks for every subsequent hold, etc.). In anotherembodiment, intermediate holds can be a combination of parameters (e.g.,amplitude and pulse width). In some embodiments, the hold may be set tobegin when both parameters are met or when one parameter is met. Inanother embodiment, one parameter cannot exceed the hold value and willremain constant until the second parameter is reached. In someembodiments, both parameters will progress according to the automatedtitration until both parameters meet the intermediate hold value, butone parameter may exceed the intermediate hold until the secondparameter reaches the intermediate hold value. The physician may havethe option to set as many or as few intermediate holds as desired.

During the automated titration between intermediate holds, the VNSsystem 11 may be fully automated or partially automated. In someembodiments, titration is performed without any intervention from eitherthe patient or the healthcare provider. This embodiment alsoautomatically detects patient side effects and intolerance and adjustsstimulation parameters to remain below the side effect threshold, as isdescribed with respect to FIG. 6B. In another embodiment, the VNS system11 may automatically adjust stimulation parameters slowly over time,without any additional intervention from the healthcare provider.Because the system may not be able to determine if stimulation causes anintolerable side effect, it may be configured to rely on the patient toswipe a magnet to indicate an intolerable level of a side effect. TheVNS system 11 may then adjust stimulation parameters in response topatient magnet activation.

For example, patients may require a total of 10±2 clinic visits over a10-week period to reach the target stimulation intensity. The frequencyof required clinic visits is bothersome to both patients and providersand creates a barrier to therapy adoption. In addition, the frequency ofrequired clinic visits extends the time required to titrate patients tothe target stimulation intensity. However, the physician may beskeptical of completely automated titration and want to ensure thepatients are not experiencing intolerable side effects and are adaptingto stimulation adequately. By allowing the physician to set theparameters, and evaluate the patient intermediately, but still allowtitration to perform automatically between visits, the time period toreach the target stimulation may be reduced, while giving the physiciansmore control over the titration process. Preferably, the number ofclinic visits needed and the overall timeframe of the titration processis reduced by only the use of intermediate holds. Any time penaltyrelated to the intermediate holds is believed to be significantly lessthan the time penalty resulting from an automated titration process thatcauses side effect and ultimately requires the patient to undergo are-titration protocol.

In step 504, titration is resumed. The physician may resume titrationusing the programmer 40 after evaluation of the patient. When thephysician resumes titration, he or she may have the option to modifystimulation parameters and/or intermediate holds. The titration mayresume using automated titration until the next intermediate hold isreached. This process may continue until the therapy parameters arereached.

FIG. 6B is a flow diagram illustrating a titration process 600 inaccordance with exemplary embodiments. When first initiating thetitration process, the neurostimulator 12 is configured to generate astimulation signal having an initial stimulation parameter set. Theinitial parameter set may comprise an initial output current, an initialfrequency, an initial pulse width, and an initial duty cycle. Thevarious initial parameter settings may vary but may be selected so thatone or more of the parameters are set at levels below a predefinedtarget parameter set level, such that the titration process is used togradually increase the intensity parameters to achieve adequateadaptation. In some embodiments, the initial frequency is set at thetarget frequency level, while the initial output current, initial pulsewidth, and initial duty cycle are set below their respective targetlevels. In one embodiment, the target parameter set comprises a 5 Hzfrequency, 250 μsec pulse width, a duty cycle of 14 sec ON and 66seconds OFF, and an output current of between 1.5 mA-3.0 mA (e.g., 2.5mA for right side stimulation and 3.0 mA for left side stimulation), andthe initial parameter set comprises 5 Hz frequency, 130 μsec pulsewidth, a duty cycle of 14 sec ON and 66 seconds OFF, and an outputcurrent of between 0.25 mA-0.5 mA. In other embodiments, the targetparameter set includes a 10 Hz frequency that is used instead of a 5 Hzfrequency. The initial parameter set may also include one or moreintermediate holds as discussed with respect to FIG. 6A. However, thisis an exemplary embodiment and these values are not intended to belimiting. Other frequencies, pulse widths, duty cycles and outputcurrents may be implemented. The initial and target parameters may varyfrom patient to patient based on the patient's sensitivity tostimulation. While the initial parameters are shown to be equal to thetarget parameters for some of the exemplary parameters (e.g., frequencyand duty cycle), some or all of the parameters may have initialparameters that differ from the target parameters.

In step 601, the stimulation system delivers stimulation to the patient.If this is the first titration session, then the stimulation would bedelivered with the initial stimulation parameter set described above. Ifthis is a subsequent titration session, then the stimulation intensitywould remain at the same level provided at the conclusion of theprevious titration session. Alternatively, the subsequent titrationsession can start at a level that is set by the physician, e.g., at thenext titration level that follows the level provided at the conclusionof the previous titration session.

In step 602, the output current is gradually increased until thestimulation results in an intolerable side effect level, the targetintensity (e.g., 2.5 mA at a pulse width of 250 μs and a frequency of 10Hz) is reached, or adequate adaptation is achieved. As described above,adequate adaptation is a composite threshold comprising one or more ofthe following: an acceptable side effect level, a target intensitylevel, and a target physiological response. In accordance with someembodiments, the target physiological response comprises a target heartrate change during stimulation. The patient's heart rate may bemonitored using an implanted or external heart rate monitor, and thepatient's heart rate during stimulation is compared to the patient'sbaseline heart rate to determine the extent of heart rate change. Inaccordance with some embodiments, the target heart rate change is aheart rate change of between 4% and 5%. If at any point during thetitration process 600 adequate adaptation is achieved, the titrationprocess ends, and the stimulation intensity which resulted in theadequate adaptation is used for ongoing maintenance dose therapydelivery.

The output current may be increased in any desired increment, but smallincrements, e.g., 0.1 mA or 0.25 mA, may be desirable so as to enablemore precise adjustments. In some cases, the output current incrementsmay be determined by the neurostimulator's maximum control capability.During the initial titration sessions, it is likely that the patient'sside effect tolerance zone boundary will be reached well before theoutput current reaches the target level or adequate adaptation isachieved. At decision step 603, if the target output current has notbeen achieved but the maximum tolerable side effects have been exceeded,the process proceeds to step 604.

In step 604, the output current is reduced one increment to bring theside effects within acceptable levels. In addition, the frequency isreduced. In embodiments in which the initial frequency was 10 Hz, instep 604, the frequency may be reduced, e.g., to 5 Hz or 2 Hz.

Next, in step 605, the output current is gradually increased again atthe reduced frequency level until the stimulation results in anintolerable side effect level or the target output current (e.g., 2.5mA) is reached. At decision step 606, if the target output current hasbeen reached and the maximum tolerable side effects have not beenexceeded, the process proceeds to step 607 where the titration sessionis concluded. The stimulation system may be programmed to continuedelivering the stimulation signal at the last parameter settingsachieved prior to conclusion of the titration session. After a period oftime, another titration session may be initiated and the process returnsto step 601. This can be any period of time sufficient to permit thepatient to adjust to the increased stimulation levels. This can be, forexample, as little as approximately two or three days, approximately oneto two weeks, approximately four to eight weeks, or any other desiredperiod of time.

In some embodiments, the titration sessions are automatically initiatedby the stimulation system or initiated by the patient without requiringany intervention by the health care provider. This can eliminate theneed for the patient to schedule a subsequent visit to the health careprovider, thereby potentially reducing the total amount of time neededfor the titration process to complete. In these embodiments, thestimulation system may include a physiological monitor, e.g., animplanted heart rate sensor, that communicates with the stimulationsystem's control system to enable the control system to detect thepatient's physiological response to the titration and automatically makeadjustments to the titration processes described herein with reduced orno inputs from the patient or health care provider. The monitoredsignals can also enable the control system to detect when the targetphysiological response has been achieved and conclude the titrationprocess. The stimulation system could in addition or alternativelyinclude a patient control input to permit the patient to communicate tothe control system that the acceptable side effect level has beenexceeded. This control input may comprise an external control magnetthat the patient can swipe over the implanted neurostimulator or otherinternal or external communication device that the patient can use toprovide an input to the control system. In these automatically-initiatedtitration sessions, the stimulation system may be configured to wait aperiod of time after completing one session before initiating the nextsession. This period of time may be predetermined, e.g., two or threedays, or programmable. In another embodiment, the stimulation system isconfigured to wait until authorization has been received beforeinitiating the next session (i.e., an intermediate hold).

Returning to decision step 606, if the target output current has notbeen reached but the maximum tolerable side effects have been exceeded,the process proceeds to step 608. In step 608, the output current isreduced one increment to restore an acceptable side effect condition,and the frequency is gradually increased until the stimulation resultsin an intolerable side effect level or the target frequency (e.g., 5 Hz)is reached. At decision step 609, if the target frequency has not beenreached but the maximum tolerable side effects have been exceeded, thefrequency is reduced to restore an acceptable side effect level and theprocess proceeds to step 607. Again, in step 607, the current titrationsession is concluded, and the stimulation system may be programmed tocontinue delivering the stimulation signal at the last parametersettings achieved prior to conclusion of the titration session.

At decision step 609, if the target frequency has been reached beforethe maximum tolerable side effects have been exceeded, the duty cycle isgradually increased until the stimulation results in an intolerable sideeffect level or the target duty cycle (e.g., 14 sec ON and 66 sec OFF)is reached, at which point the process proceeds to step 607 and thetitration session is concluded and ongoing stimulation delivered at thelast intensity eliciting acceptable side effect levels.

Returning to decision step 603, if the target output current has beenachieved before the maximum tolerable side effects are exceeded, theprocess proceeds to step 611. In step 611, the pulse width is graduallyincreased until the stimulation results in an intolerable side effectlevel or the target pulse width (e.g., 250 μsec) is reached. In someembodiments, before step 611, the output current is reduced (e.g., by upto 50%), and the pulse width may be increased in step 611 at thatreduced output current. After the target pulse width is achieved, theoutput current may be restored to the target output current. In otherembodiments, the output current may be reduced (or may be retained atthe reduced level established prior to step 611, as described above),and the frequency and duty cycle are gradually increased in step 613 atthat reduced output current. This reduction in output current afterachieving the target output current may enable the patient to maintaintolerability with increasing pulse width, frequency, and duty cycle insubsequent titration steps.

At decision step 612, if the target pulse width has not been achievedbefore the maximum tolerable side effects have been exceeded, the pulsewidth is reduced to restore an acceptable side effect level and theprocess proceeds to step 607. Again, in step 607, the current titrationsession is concluded.

If at decision step 612, the target pulse width has been achieved beforethe maximum tolerable side effects have been exceeded, the processproceeds to step 613. In step 613, the frequency and/or duty cycle areincreased until the stimulation results in an intolerable side effectlevel or the target frequency and target duty cycle are reached. Thefrequency and duty cycle can be increased in step 612 simultaneously,sequentially, or on an alternating basis.

At decision step 614, if the target frequency and/or target duty cyclehave not been achieved before the maximum tolerable side effects havebeen exceeded, the pulse width and/or frequency are reduced to restorean acceptable side effect level, and the process continues to step 607and the titration session is concluded. In some embodiments, theconclusion of the titration session represented in step 607 indicates anintermediate hold has been reached. A new titration session could thenbe initiated after visiting a physician to release the intermediatehold.

At decision step 614, if the target pulse width and target frequencyhave been achieved before the maximum tolerable side effects have beenexceeded, all of the stimulation parameters will have reached theirtarget levels and the titration process concludes at step 615. Thestimulation therapy may proceed with the maintenance dose at the targetstimulation levels. In some embodiments, the target frequency and dutycycle achieved are for a given titration session with an intermediatehold. In this case, the patient would visit a health care provider orphysician for an evaluation. The physician would then release the holdon the titration processes or initiate the beginning of therapy.

In some embodiments, in step 604, instead of reducing the frequency inorder to facilitate increase of the output current, the pulse width maybe reduced. For example, embodiments where the target pulse width is 250μsec, the pulse width may be reduced, e.g., to 150 μsec or less. Then,the method proceeds to step 605, in which the output current isgradually increased again at the reduced pulse width level until thestimulation results in an intolerable side effect level or the targetoutput current (e.g., 2.5 mA) is reached.

Therapy can also be autonomously titrated by the neurostimulator 12 inwhich titration progressively occurs in a self-paced, self-monitoredfashion. The progression of titration sessions may occur on anautonomous schedule or may be initiated upon receipt of an input fromthe patient. Ordinarily, the patient 10 is expected to visit hishealthcare provider to have the stimulation parameters stored by theneurostimulator 12 in the recordable memory 29 reprogrammed using anexternal programmer. Alternatively, the neurostimulator 12 can beprogrammed to automatically titrate therapy by up titrating the VNSthrough periodic incremental increases using titration sessions asdescribed above. The titration process 600 will continue until theultimate therapeutic goal is reached.

Following the titration period, therapeutic VNS, as parametricallydefined by the maintenance dose operating mode, is delivered to at leastone of the vagus nerves. The stimulation system 11 delivers electricaltherapeutic stimulation to the cervical vagus nerve of a patient 10 in amanner that results in creation and propagation (in both afferent andefferent directions) of action potentials within neuronal fibers ofeither the left or right vagus nerve independent of cardiac cycle.

FIG. 7A is a simplified block diagram of an implanted neurostimulationsystem 700, according to an exemplary embodiment. The implantedneurostimulation system 700 comprises a control system 702 comprising aprocessor programmed to operate the system 700, a memory 703, anoptional physiological sensor 704, and a stimulation subsystem 706. Thephysiological sensor 704 may be configured to monitor any of a varietyof patient physiological signals, and the stimulation subsystem 706 maybe configured to deliver a stimulation signal to the patient. In oneexample, the physiological sensor 704 comprises an ECG sensor or anaccelerometer for monitoring heart rate, and the stimulation subsystem706 comprises a neurostimulator 12 programmed to deliver ON-OFF cyclesof stimulation to the patient's vagus nerve. The implanted system 700may include a patient input sensor 705, described in more detail below.

The control system 702 is programmed to activate the neurostimulator 12to deliver stimulation signals at varying stimulation intensities to thepatient and to monitor the physiological signals in response to thosedelivered stimulation signals.

The external programmer 707 shown in FIG. 7A may be utilized by aclinician or by the patient for communicating with the implanted system700 to adjust parameters, activate therapy, retrieve data collected bythe system 700, or provide other input to the system 700. In someembodiments, the external programmer 707 may be used remotely from theimplanted system 700 (e.g., when the patient is not at a clinic). Forexample, instead of the patient coming into the clinic for a check-upduring a titration hold, the clinician may check on the patient remotely(e.g., phone call, video call, etc.). The clinician could then use theexternal programmer 707 to activate the next titration session or modifyparameters of the titration. In some embodiments, the externalprogrammer 707 may provide an alert indicating the patient has reached atitration hold. In some embodiments, the patient receives an alertindicating a titration hold has been reached (e.g., email, text message,etc.). In some such embodiments, the external programmer 707 may includecommunication circuitry adapted to communicate over a long distanceusing one or more protocols (e.g., cellular, Internet, etc.). In someembodiments, the external programmer 707 may be configured to programthe implanted system 700 with a prescribed time or window of time duringwhich titration sessions may be initiated, as described in furtherdetail below with respect to FIGS. 16 and 17. This can be used, forexample, to prevent a titration session from occurring at night when thepatient's sleep is likely to be disturbed by the increase in stimulationintensity and resulting side effects.

Patient inputs to the implanted system 700 may be provided in a varietyof ways. The implanted system 700 may include a patient input sensor705. As described above, a patient magnet 730 may be used to provideexternal input to the system 700. When the patient magnet 730 is placedon the patient's chest in close proximity to the implanted system 700,the patient input sensor 705 will detect the presence of the magneticfield generated by the patient magnet 730 and provide a control input tothe control system 702. The system 700 may be programmed to receivepatient inputs to set the time of day during which titration sessionsare to be initiated.

In other embodiments, the patient input sensor 705 may comprise a motionsensor, such as an accelerometer, which is configured to detect tappingon the surface of the patient's chest. The patient may use finger tapsin one or more predetermined patterns to provide control inputs to theimplanted system 700. For example, when the motion sensor detects threerapid taps to the patient's chest, that may trigger an operation on theimplanted system 700 (e.g., to initiate a titration session).Alternatively, if the motion sensor detects a predetermined pattern oftaps during a titration session, the implanted system 700 will interpretthose taps as a patient input indicating that the patient's tolerancezone boundary has been exceeded.

In other embodiments, the patient input sensor 705 may comprise anacoustic transducer or other sensor configured to detect acousticsignals. The system 700 may be programmed to interpret the detection ofcertain sounds as patient inputs. For example, the patient may utilizean electronic device, such as a smartphone or other portable audiodevice, to generate one or more predetermined sequences of tones. Thesystem 700 may be programmed to interpret each of these sequences oftones as a different patient input.

The titration of the stimulation signal delivery and the monitoring ofthe patient's physiological response (e.g., heart rate) may beadvantageously implemented using a control system 702 in communicationwith both the stimulation subsystem 706 and the physiological sensor704, such as by incorporating all of these components into a singleimplantable device 700. In accordance with other embodiments, anexternal control system 712 may be implemented in a separate implanteddevice or in an external programmer 720 or other external device, asshown in FIG. 7B to provide control over and communication with animplanted physiological sensor 714 and a stimulation subsystem 716similar to those describe with regard to FIG. 6A. The externalprogrammer 720 in FIG. 7B may be utilized by a clinician or by thepatient for adjusting stimulation parameters. The external programmer720 may be in wireless communication with the implanted medical device710, which includes the stimulation subsystem 716 and a memory 713. Inthe illustrated embodiment, the physiological sensor 714 is incorporatedinto the implanted medical device 710, but in other embodiments, thesensor 714 may be incorporated into a separate implanted device, may beprovided externally and in communication with the external programmer720, or may be provided as part of the external programmer 720.

When monitoring the patients, the physician uses the external programmer707 to connect with the implantable medical device 710. However, in someimplementations, the physician must manually connect the externalprogrammer 707 to each implantable medical device 710 to performtitration functions (e.g., change parameter settings, titration holdsand settings, etc.), which can be burdensome on physicians, as well asthe clinic. FIGS. 8-10 address this issue, according to exampleembodiments, by providing a dashboard capable of monitoring a pluralityof patients, even when the patients are not in the clinic.

FIG. 8 is a titration assist management dashboard 800, according to anexemplary embodiment. The titration assist management dashboard 800operates on a device 802 with a display 804. The display 804 providesthe dashboard 800 which includes information relating to patient name806, patient status 808, patient priority 810 and patient notes 812.

The device 802 includes a processor, memory, a communication circuit,and various input and output circuits. The device 802 may be aprogramming computer (e.g., programming computer 41, external programmer707) that is in direct communication with a programming wand (e.g.,programming wand 42). In some embodiments, the device 802 may be acomputer, a tablet, a handheld device, a wearable, etc. In someembodiments, the device 802 is capable of communicating directly with animplantable medical device (e.g., telemetry). In some embodiments, thedevice 802 that is capable of communicating with a secondary device(e.g., a programming computer) that communicates with an implantablemedical device. In some embodiments, the device 802 can communicate witha remote device that is not located at the physician's office, such as ahome monitor. The device 802 may communicate with the secondary devicevia telemetry, a wired connection, or another device/method ofcommunication. In some embodiments, the device 802 is in communicationwith a website, server, program, etc. that allows the device 802 toaccess the dashboard 800. For example, the dashboard 800 may beaccessible on multiple devices 802 at the same time.

The dashboard 800 includes information relating to patient name 806,patient status 808, patient priority 810, and/or patient notes 812. Thedashboard 800 compiles patient information when a patient is set up on atitration assist program. Once the patient information is in thedashboard 800, the dashboard 800 is able to monitor patient statuswithout being in communication with the implantable medical device byknowing the parameters of the titration assist and updating thedashboard according to the titration assist parameters, in someimplementations.

For each patient, the dashboard 800 provides patient name 806, patientstatus 808, patient priority 810, and/or patient notes 812. In order touse the dashboard 800, a user (e.g., physician, nurse, medicalassistant, etc.) may provide log in credentials. In some embodiments,the amount or detail of information provided may vary based on the login information provided. For example, the physician may have access toall the information provided on the dashboard 800, while the informationprovided to a nurse or medical assistant may be more limited.

The patient name 806 provided on the dashboard 800 may be the actualname of the patient, or a means of identifying the patient whilemaintaining anonymity of the patient (e.g., patient identificationnumber, etc.). In some embodiments, the patient name 806 may alsoprovide information relating to general patient information (e.g., homeaddress, contact information, medical history, age, gender, insuranceinformation, etc.). While all this information may not be present on amain screen of the dashboard 800 (e.g., as shown in FIG. 8), the usermay be able to access the additional information by selecting a specificpatient.

The patient status 808 provided on the dashboard 800 is a status of theprogression of the titration based on the titration assist parametersestablished during interrogation of the implantable medical device. Thepatient status 808 may include a stimulation parameters (e.g.,amplitude, frequency, pulse width, etc.). In some embodiments, thepatient status 808 may also indicate if a HOLD is present in thetitration progression, an indication of the weeks that have passes sincetitration has started, or another indication of the time of titration.The dashboard 800 is able to update the patient status 808 based on thesettings of titration, such as updating the patient status 808 toindicate a hold is present.

The dashboard 800 may also include patient notes 812. The patient notes812 may include a plurality of information relating to the patient,titration, and other information the physician feels may be pertinent.For example, the patient notes 812 may include the aggression profilethat was selected for the patient, initial titration parameters, targetstimulation parameters, settings for stimulation increases, titrationhold settings, a parameter setting profile, patient side effects, etc.The patient notes 812 may be a text box or a plurality of text boxeswhere the user can insert a variety of notes. In some embodiments, thepatient notes 812 are a plurality of check boxes or other selectionmechanisms that provides a list of parameters, settings, side effects,etc. that can be selected. In some embodiments, the patient notes 812are a combination of check boxes and text boxes to provide diverse meansof recording patient notes 812. The patient notes 812 may all be presenton the dashboard 800. In some embodiments, only a portion of thepatients notes 812 are provided on a main screen of the dashboard 800.In some embodiments, the user may be able to select which patient notes812 are present on the main screen of the dashboard 800. In someembodiments, a default set of patient notes 812 are present on the mainscreen of the dashboard 800. In some embodiments, the dashboard 800 cancreate patient notes based on the patient status 808. For example, ifthe patient status 808 is updated to indicate a hold has been reached,the patient notes 812 may be updated to indicate a follow up appointmentor call needs to be scheduled.

The patient priority 810 indicates a likelihood of the patient needingattention (e.g., most likely to need a clinical visit). The patientpriority 810 may be based on a combination of patient status 808,patient information contained within the patient name 806, and patientnotes 812. The patient status 808, patient information contained withinthe patient name 806, and patient notes 812 may receive a value based onthe information contained within. The patient priority 810 may be aweighted combination of the values of the patient status 808, patientinformation contained within the patient name 806, and patient notes812. In some embodiments, the information contained in the patient notes812 may be individually valued and/or weighted based on the informationcontained (e.g., aggression profile, target stimulation, side effects,etc.). Some side effects may be indicated as more severe than others,and the dashboard 800 may assign a different value or weight relating todifferent side effects. In addition, patients may be more prone to sideeffects during different stages of titration based on the intensity oftitration, which again could receive different values or weighting bythe dashboard 800. Patients may also be more or likely to developvarious side effects, or experience the side effects more severely basedon tolerance; this can be taken into account by the dashboard 800 whendetermining patient priority 810.

The patient priority 810 may be selected depending on a value of theweight profile crossing one or more thresholds defining various patientpriorities 810. In some embodiments, the patient priority 810 may beindependent of a priority calculated for another patient (i.e., multiplepatients may have the same priority level). In some embodiments, thepatient may be compared to some or all of the other patients in thedashboard 800 to provide a unique patient priority 810 to each patient.In some embodiments, custom patient priorities 810 may be established bythe physician based on physician knowledge that may not be recognized bythe dashboard 800.

The dashboard 800 may also provide addition functions for the physicianto interact with and analyze patient information. In some embodiments,the dashboard 800 can provide a log of interactions with the dashboard800. In some embodiments, the dashboard 800 provides a log ofinteractions based on the patient, the person who was logged in,insurance, etc.

In some embodiments, the dashboard 800 provides controls for thephysician to collect and analyze physiological data of the patient,modify stimulation parameters, and monitor and modify stimulation holds.In some embodiments, the dashboard 800 collects physiological patientdata through remote communication with the implantable medical device ofthe patient or a home monitoring system of the patient. In someembodiments, the physiological data can be updated for a patient in realtime. In some embodiments, the physiological data is provided to thedashboard 800 periodically (e.g., daily, weekly, etc.).

In some embodiments, the dashboard 800 provides functions allowing auser to modify stimulation parameters. The stimulation parameters can bemodified by changing an aggression profile, target parameter settings,titration step settings, etc. In some embodiments, the stimulationparameters can be remotely modified at any time. The patient may benotified to provide an update via a home monitoring unit. In someembodiments, the stimulation parameters are limited to remotemodifications during specific times of the titration process (e.g.,titration holds). In some embodiments, the remote modification of thestimulation parameters is limited. For example, the parameters can onlybe modified by certain predefined amounts, maximum amounts, or otherlimitations. In some embodiments, the modified stimulation parametersare updated in the implantable medical device with a home monitoringdevice. In some embodiments, the patient is alerted of an update andmust take action to update the implantable medical device. In someembodiments, the implantable medical device is automatically updated.

In some embodiments, the physician is able to modify the hold settingsof the titration for any given patient. In some embodiments, thephysician can initiate a hold, clear a hold, modify the parameter levelat which a hold is initiated, add additional holds, or modify the holdsin other ways. Therefore, if the physician notices physiological data ofthe patient is indicating adverse side effects, if the dashboard 800alerts the physician of adverse side effects, if the patient contactsthe physician regarding adverse side effects, etc., then the physiciancan initiate a hold for the titration settings of the patient using thedashboard 800. In some embodiments, the physician can initiate a holdwith parameters different than the parameters that caused adverse sideeffects. By initiating the hold, the physician can schedule time to talkto the patient on the phone or in the office without allowing theadverse side effects to continue or worsen.

In some embodiments, the physician can clear a hold remotely using thedashboard 800. For example, a physician may talk to the patient over thephone to determine if the patient is experiencing any adverse sideeffects once the dashboard 800 indicates a hold for the patient. Thephysician can then remotely clear the hold if no adverse side effectsare being experienced by the patient.

In some cases, after the initial parameter and titration settings havebeen established, the physician may determine that a patient is more orless prone to side effects than initially determined. Accordingly, insome embodiments, the physician is able to modify the parameter settingsassociated with a future hold (e.g., instead of having a hold at 1.5 mA,have a hold at 2.0 mA), without modifying the titration settings, suchthat the hold occurs sooner or later that initially established. In someembodiments, the physician can add or remove a future hold instead of,or in addition to, modifying the parameter settings associated with ahold.

In some embodiments, the holds are updated in the implantable medicaldevice with a home monitoring device of the patient. In someembodiments, the patient is alerted of an update and must take action toupdate the implantable medical device. In some embodiments, theimplantable medical device is automatically updated.

FIG. 9 is a patient titration graph 900 of the titration assistmanagement dashboard 800 of FIG. 8, according to an exemplaryembodiment. The user can select a patient on the dashboard 800 to viewin further detail. By selecting a patient, the user can see thetitration graph 900 that is specific to the selected patient. The graph900 includes an x-axis 902, a y-axis 904, a stimulation level 906, oneor more holds 908, and a current stimulation setting 910.

The x-axis 902 is a unit of time (e.g., days, weeks, months, etc.),while the y-axis 904 is a parameter of stimulation (e.g., amplitude,frequency, duty cycle, etc.). In some embodiments, the user can changethe units of the x-axis 902 and the y-axis 904 to provide alternativeviews of the titration settings. The stimulation level 906 is shownbased on the units set for the x-axis 902 and the y-axis 904. While thestimulation level 906 is shown in FIG. 9 as increasing uniformly, thestimulation level 906 is based on the titration parameters set forth,which may not increase in a uniform fashion.

The stimulation level 906 also includes the titration holds 908 thatwere established during set up of titration. The titration holds 908 maybe set at equal intervals or may be set at varying intervals, based onthe requirements set forth during set up. In some embodiments, thetitration graph 900 also includes a marker showing the currentstimulation setting 910. The current stimulation setting 910 indicatesthe progression of the titration so the user can easily see how soon thenext hold 908 will occur and the current stimulation setting 910, pastand future stimulation levels 906.

FIG. 10 is a flowchart of a process 1000 for managing patients using thetitration assist management dashboard 800, according to an exemplaryembodiment. The process 1000 includes receiving a plurality of patientinformation at 1002, evaluating each patient at 1004, determining astatus of each patient at 1006, determining a priority of each patientat 1008, and sorting the patients based on user input at 1010.

The titration assist management dashboard 800 receives the plurality ofpatient information at 1002. In some embodiments, the titration assistmanagement dashboard 800 receives patient information relating to asingle patient one at a time. In some embodiments, the titration assistmanagement dashboard 800 receives patient information relating tomultiple patients at once. In some embodiments, the titration assistmanagement dashboard 800 receives patient information by wirelesslycommunicating with an individual implantable medical device for eachpatient. In some embodiments, the titration assist management dashboard800 receives patient information via wired or wireless communicationwith a programming wand. In some embodiments, the titration assistmanagement dashboard 800 receives patient information via wirelesscommunication with a remote device (e.g., home monitor, etc.). In someembodiments, the titration assist management dashboard 800 receivespatient information via communication with another device located in thephysician's office or the patient's home. In some embodiments, a user ofthe titration assist management dashboard 800 must actively prompt thetitration assist management dashboard 800 to receive patientinformation. In some embodiments, the titration assist managementdashboard 800 automatically collects patient information when certaincriteria are met (e.g., device with patient information connected,device with patient information identified, patient is not currently intitration assist management dashboard, etc.). The patient informationmay include patient name, address, number, insurance information,titration assist parameters, patient notes 812, etc.

The titration assist management dashboard 800 evaluates each patientbased on the patient information at 1004. The titration assistmanagement dashboard 800 may evaluate the patient information todetermine if any required information is missing (e.g., name, insuranceinformation, titration settings, etc.). In some embodiments, thetitration assist management dashboard 800 prompts a user to enter themissing information (e.g., a pop-up screen, alert, etc.). In someembodiments, the titration assist management dashboard 800 flags apatient as having missing information (e.g., change in color, marking bypatient, etc.). In some embodiments, the titration assist managementdashboard 800 evaluates the patient information to determine if thepatient is likely to obtain side effects from titration or needadditional contact with the physician. In some embodiments, thetitration assist management dashboard 800 evaluates patient height,weight, gender, titration settings, notes etc. to determine if thepatient is likely to obtain side effects from titration or needadditional contact with the physician.

The titration assist management dashboard 800 determines a status ofeach patient at 1006. As described above, the patient status is thestatus of the progression of the titration based on the titration assistparameters established during interrogation of the implantable medicaldevice. The patient status may include a stimulation parameters (e.g.,amplitude, frequency, pulse width, etc.). In some embodiments, thepatient status may also indicate if a HOLD is present in the titrationprogression, an indication of the weeks that have passes since titrationhas started, or another indication of the time of titration. Thetitration assist management dashboard 800 is able to update the patientstatus based on the settings of titration, such as updating the patientstatus to indicate a hold is present. The patient status may be updatedperiodically (e.g., daily, weekly, when a titration setting changes,etc.) without being in communication with the implantable medical deviceby knowing the parameters of the titration assist and updating thedashboard according to the titration assist parameters that are recordedin the titration assist management dashboard 800.

The titration assist management dashboard 800 determines a priority ofeach patient at 1008, in some implementations. The patient priorityindicates a likelihood of the patient needing attention (e.g., mostlikely to need a clinical visit). The patient priority may be based on acombination of patient status, patient information contained within thepatient name, and patient notes. The patient status, patient informationcontained within the patient name, and patient notes may receive a valuebased on the information contained within. The patient priority may be aweighted combination of the values of the patient status, patientinformation contained within the patient name, and patient notes. Insome embodiments, the information contained in the patient notes 812 maybe individually valued and/or weighted based on the informationcontained (e.g., aggression profile, target stimulation, side effects,etc.). Some side effects may be indicated as more severe than others,and the dashboard 800 may assign a different value or weight relating todifferent side effects. In addition, patients may be more prone to sideeffects during different stages of titration based on the intensity oftitration, which again could receive different values or weighting bythe dashboard. Patients may also be more or less likely to developvarious side effects, or experience the side effects more severely,based on tolerance; this can be taken into account by the titrationassist management dashboard 800 when determining patient priority.

The patient priority may be selected depending on a value of the weightprofile crossing one or more thresholds defining various patientpriorities. In some embodiments, the patient priority may be independentof a priority calculated for another patient (i.e., multiple patientsmay have the same priority level). In some embodiments, the patient maybe compared to some or all of the other patients in the titration assistmanagement dashboard 800 to provide a unique patient priority to eachpatient. In some embodiments, custom patient priorities may beestablished by the physician based on physician knowledge that may notbe recognized by the titration assist management dashboard 800.

The titration assist management dashboard 800 may indicate patientpriority in a variety of ways. In some embodiments, the patients arecolor coded based on patient priority (e.g., red for high priority,green for low priority, etc.). In some embodiments, the patient priorityis a number. In some embodiments, the patient priority is a symbol,marker, or other visual indication of patient priority.

The titration assist management dashboard 800 sorts the patients basedon user input at 1010. The user may be able to select a default settingfor sorting the patients, such that if no sorting has been selected, thepatients will be sorted according to the default setting. The user maybe able to sort the patients based on patient name, patient information,patient status, patient priority, etc. In some embodiments, the patientscan be sorted in ascending or descending order based on the selectedcriteria.

By creating a dashboard (e.g., dashboard 800), a physician can monitor aplurality of patients with a single device. The physician is able toeasily view the status of any patient without having to interrogatetheir implantable medical device. In addition, if a patient calls thephysician's office, the physician can determine what the stimulationparameters are for titration and may be able to evaluate the patientover the phone or recommend that the patient come into the office for acheck-up based on urgency and severity. The physician can also takenotes on the dashboard based on information received from the patientduring the call.

As discussed above, the VNS system 11 may perform fully automated orpartially automated titration of VNS stimulation parameters. Forexample, in some arrangements, the VNS system 11 performs automatedtitration of VNS stimulation parameters between an initial stimulationintensity and a hold intensity prescribed by the patient's physician(e.g., by making small, periodic stimulation intensity increases betweenthe initial and hold intensities). Once the hold intensity is reached,the patient must visit the physician. The physician evaluates thepatient for side effects and decides whether to remove the hold andcontinue titration. This process is continued until the stimulationreaches a physician-prescribed target intensity. In other arrangements,the physician sets an initial stimulation intensity and a targetstimulation intensity. The VNS system 11 then performs titration byautomatically making small, periodic stimulation intensity increasesbetween the initial and target intensities such that the patient'snervous system is allowed to accommodate to each new intensity. Once thetarget intensity is achieved, the patient returns to the physician forfinal intensity adjustments. As such, evaluation of the heart rateeffects at higher stimulation intensities occur while the patient is inthe clinic environment with appropriate physiological monitoring.

One advantage of performing titration in this manner is that this methodof titration reduces or eliminates patient and physician workloads asthe patient does not need to visit the clinic for any titrationadjustment. The frequency of titration can also occur at a rate ofadjustment (e.g., multiple small titration step increases per day) thatwould otherwise not be practically feasible for patients using existingalternatives of on-site visits for every programmed adjustment.Moreover, this method of titration assures that the patient receivestherapeutic levels of stimulation quickly while simultaneouslyminimizing the likelihood of serious adverse effects (e.g., minimizingthe chances of the patient developing symptomatic bradycardia). Toillustrate, a traditional titration method may require 8-12 clinicvisits, 12-18 hours of programming time, and 24-48 hours of patient timeexposure. Yet, the traditional titration method may only allow for 6-10therapy adjustments with 10-12 weeks required until the stimulationintensity reaches therapeutic levels. By contrast, the present systemsand methods for titration may require only 2 clinic visits, 2 hours ofprogramming time, and 6 hours of patient time exposure, while allowingfor 25+ therapy adjustments with only 4-6 weeks required until thestimulation intensity reaches therapeutic levels.

Moreover, in various embodiments, the VNS system 11 may be programmablewith high resolution stimulation parameters that enable physicians touse an optimal set of stimulation parameters (e.g., current amplitude,frequency, pulse width, ON-time and OFF-time). As an illustration,physicians may be able to fine-tune therapy around the patient's neuralfulcrum (i.e., an operating point formed by a combination of stimulationintensity and duty cycle that gives rise to a small and repeatablereduction in heart rate) using the high resolution parameters. Thesehigh resolution stimulation parameters improve the titration experiencefor the patient by enabling smaller intensity steps, which allowspatients to reach a therapeutic range without requiring a clinic visitfor every stimulation adjustment.

Additionally, automatic adjustment of the stimulation parameters mayoccur according to settings programmed by the physician or modified orselected by the physician from factory settings. For example, thephysician may be able to select from specific parameters provided by theVNS system 11 or from a parameter range provided by the VNS system 11.As an illustration, the physician may be able to select between 0.125 mA(for 0.0 to 1.875 mA initial to target intensities) and 0.25 mA (for 2.0to 3.5 mA target intensities) current amplitude increments; 2, 3, 4, 5,6, 7, 8, 9, 10, 15, and 20 Hz frequency increments; and 130, 150, 180,210, 250, 275, 300, 370, and 500 μs pulse width increments, with thestimulation occurring according to a default duty cycle (e.g., 14seconds ON and 66 seconds OFF, with a 2 second ramp-up and a 2 secondramp-down). Alternatively, the automatic adjustment may occur basedentirely or almost entirely on factory setting, such as on afactory-adjustable fixed time interval (e.g., four steps per day),during fixed time periods (e.g., only during the daytime when thepatient is less likely to be asleep, as described below with referenceto FIGS. 16 and 17), according to fixed trajectories (e.g., as shown inFIG. 13), and so on. The VNS system 11 may then determine whether anychanges should be made to the stimulation parameters and, if so, whichchanges should be made during the titration process.

As an example, a physician may set (e.g., via the external programmer40) the initial stimulation intensity (e.g., zero stimulation, with a 0mA amplitude, 60 μs pulse width, and 5 Hz frequency) and the targetstimulation (e.g., 1.5-2.0 mA amplitude, 250 μs pulse width, and 5 Hzfrequency). The VNS system 11 may then dictate titration according to analgorithm such that four titration steps (e.g., 0.125 mA, 30 μsec,and/or 0.1 Hz steps, which result in smooth intensity increases overtime) are implemented a day with no changes permitted between 1:00 and6:00 AM (e.g., to avoid the possibility that the patient may go to sleepwith no side effects but later wake up from the side effects, such as acough). Once the target stimulation is reached, the physician may makefurther adjustments as the patient will likely tolerate the adjustmentsdue to the patient's nervous system having become accommodated to thestimulation.

In various embodiments, the VNS system 11 may be programmed (e.g., bythe external programmer 40 or the recordable memory 29 can containcertain instructions when the neurostimulator 12 is implanted) toperform the titration according to a stimulation profile adapted toreduce patient side effects during the titration process. As anillustration, FIG. 11 is a patient titration graph 1100 incorporating a“dwell point,” according to an exemplary embodiment. The graph 1100includes an x-axis 1102 and a y-axis 1104. The x-axis 1102 is a unit oftime (e.g., days, weeks, months, etc.), while the y-axis 1104 is aparameter of stimulation (e.g., amplitude, frequency, duty cycle, etc.).In various embodiments, the titration graph 1100 may be incorporated ina user interface displayed to a physician (e.g., on the externalprogrammer 40 or other computing device) during the titrationconfiguration process.

The graph 1100 includes three titration rates at which at least onestimulation parameter (e.g., output current, frequency, pulse width,duty cycle, etc.) is increased. In various embodiments, each of thethree titration rates are configured such that the at least onestimulation parameter is gradually increased. The titration according toFIG. 11 initially occurs at a first rate 1106 until the at least onestimulation parameter reaches a first target value 1108. Subsequently,the titration shifts to a second rate 1110, which is less than the firstrate 1106. Because the at least one parameter is increased more slowlyduring this portion of the titration, the second rate 1110 marks a“dwell point” in the graph 1100. The titration occurs according to thesecond rate 1110 until the at least one stimulation parameter reaches asecond target value 1112. Once the second target value 1112 is reached,the titration occurs at a third rate 1114. The third rate 1114 isgreater than the second rate 1110 and may be the same as the first rate1106 (e.g., as shown in FIG. 11) or different from the first rate 1106.The at least one stimulation parameter increases according to the thirdrate 1114 until, e.g., a titration hold is reached or the stimulation isfully titrated.

In some embodiments, the first rate 1106, second rate 1110, and thirdrate 1114 may be continuous rates, as shown in FIG. 11. In otherembodiments, the first rate 1106, second rate 1110, and third rate 1114may be step functions (e.g., with steps corresponding to smallstimulation intensity increases that occur several times each day, suchas four times a day). In such embodiments, the first rate 1106 and thirdrate 1114 may be greater than the second rate 1110 because, e.g., thefirst rate 1106 and third rate 1114 include greater stimulationparameter increases in each step and/or include steps that last forshorter periods of time compared to the steps of the second rate 1110.Additionally, in certain embodiments, the second rate 1110 may insteadbe a prolonged hold on the titration such that the at least onestimulation parameter is kept constant for a certain period of time(e.g., 1-7 days), after which the titration resumes at the third rate1114. Moreover, in certain embodiments, the second rate may depend onthe aggressiveness of a titration profile used to accomplish titrationof the neurostimulation, the profile determined either by the physicianor as determined by the VNS system 11 itself.

Performing titration according to the graph 1100 may be beneficial forpatients because it has been observed that a patient's adaptation totitration is non-linear. Specifically, there is a period in thestimulation intensity progression (e.g., at a stimulation amplitude of0.75 to 1.0 mA) where the patient's adaptation tends to stall and thepatient requires additional time for adaptation to occur. Accordingly,incorporating the “dwell point” via the lowered second rate 1110 duringthis period (e.g., between the stimulation amplitudes of 0.75 to 1.0 mA,where 0.75 mA is the first target value 1108 and 1.0 mA is the secondtarget value 1112) allows a patient to more smoothly adapt to thestimulation intensity while minimizing deleterious side effects.

In various embodiments, the VNS system 11 implements titrationincorporating a dwell point automatically. In other embodiments,however, the VNS system 11 may incorporate a dwell period based onexternal input (e.g., from a physician using the programmer 40). Forexample, a physician may program the VNS system 11 to titrate accordingto the second rate for a certain number of days, until a certainstimulation amplitude is reached, and so on.

FIG. 12 is a flowchart of a titration process 1200 (e.g., implemented bythe VNS system 11) that incorporates a titration dwell point, accordingto an exemplary embodiment. First, the VNS system 11 delivers a firstneurostimulation signal with a first set of parameters at 1202. Thefirst set of parameters has a first value for, e.g., at least one of anoutput current, frequency, pulse width, or duty cycle. The VNS system 11then increases at least one of the first parameters at a first rate(e.g., the first rate 1106) until the at least one parameter reaches afirst target value (e.g., the first target value 1108) at 1204. Once thefirst target value is reached, the VNS system 11 ceases delivery of thefirst neurostimulation signal at 1206.

Subsequently, the VNS system 11 delivers a second neurostimulationsignal with a second set of parameters at 1208. The second set ofparameters has a second value for, e.g., at least one of output current,frequency, pulse width, or duty cycle, where the second value is equalto the first target value. For the purposes of this disclosure, a firstvalue may be considered “equal” to a second value if the first value isexactly equal to the second value or if the first and second values arewithin a threshold of each other (e.g., five percent). The VNS system 11increases at least one of the second parameters at a second ratedifferent from the first rate (e.g., the second rate 1110) until the atleast one parameter reaches a second target value (e.g., the secondtarget value 1112) at 1210. For example, as discussed above, the secondrate may be less than the first rate, or the second rate may be anapplication of a substantially constant neurostimulation signal for aperiod of time. As another example, as also discussed above, the firstand second rates may be stepwise functions, where the second steps areapplied for greater periods of time than the first steps.

Further, as shown in FIG. 11, once the second target value is reached,the VNS system 11 may cease delivery of the second neurostimulationsignal and apply a third neurostimulation signal with a third set ofparameters having a third value equal to the second target value. TheVNS system 11 may then increase at least one of the third parameters ata third rate that is equal to the first rate or, alternatively,different from the first rate and the second rate. In some embodiments,the VNS system 11 may also implement a hold between ceasing delivery ofthe second neurostimulation signal and applying the thirdneurostimulation signal.

As another example of titration adapted to reduce adverse side effects,FIG. 13 is a patient titration graph 1300 illustrating differenttitration aggressiveness profiles, according to an exemplary embodiment.The graph 1300 includes an x-axis 1302 and a y-axis 1304. The x-axis1302 is a unit of time (e.g., days, weeks, months, etc.), while they-axis 1304 is a parameter of stimulation (e.g., amplitude, frequency,duty cycle, etc.). In various embodiments, the titration graph 1300 maybe incorporated in a user interface displayed to a physician (e.g., onthe external programmer 40 or other computing device) during thetitration configuration process. The aggressiveness profiles shown ingraph 1300 are a medium aggressiveness profile 1306, a highaggressiveness profile 1308, and a low aggressiveness profile 1310. Eachof the aggressiveness profiles 1306, 1308, and 1310 is associated with arate of titration (e.g., an increment value between initial stimulationparameters and a target value 1312), where the rate of titration for thehigh aggressiveness profile 1308 is greater than the rate of titrationfor the medium aggressiveness profile 1306, which in turn is greaterthan the rate of titration for the low aggressiveness profile 1310.Accordingly, patients using the high aggressiveness profile 1308transition to a target value 1312 from initial stimulation parametersfor within a shortest time interval (e.g., 30 days), while patientsusing the low aggressiveness profile 1310 transition to the target value1312 from initial stimulation parameters within a longest time interval(e.g., 60 days), and patients using the medium aggressiveness profile1306 transition to the target value 1312 from initial stimulationparameters within an interval sometime in between the highaggressiveness profile 1308 and the low aggressiveness profile 1310(e.g., 45 days). Alternatively, or additionally, the low aggressivenessprofile 1310, the medium aggressiveness profile 1306, and the highaggressiveness profile 1308 may be associated with increasingly greatertarget intensity values.

With each profile 1306, 1308, and 1310, at least one stimulationparameter (e.g., stimulation current amplitude, pulse width, frequency,duty cycle, etc.) is increased (e.g., gradually increased) according tothe rate of titration of the profile 1306, 1308, or 1310. In someembodiments, the rate of titration may be linear and continuous for eachof the aggressiveness profiles 1306, 1308, and 1310, as shown in FIG.13. In other embodiments, each rate of titration may instead beimplemented as a step function where, e.g., the high aggressivenessprofile 1308 includes steps that are the closest together in time andthe low aggressiveness profile 1310 includes steps that are the furthestapart in time. For example, the titration may occur according to a fixedtime interval during the daytime hours, where the number of stepsimplemented during that fixed time interval depends on which profile1306, 1308, or 1310 is used.

The profiles 1306, 1308, and 1310 may also be linear, or the profiles1306, 1308, and 1310 may be non-linear (e.g., incorporating a dwellperiod, as shown in FIG. 11 above, or steeper after the stimulationamplitude exceeds a threshold after which intolerance is less likely,such as 2.0 mA). Additionally, in certain embodiments, the shape, stepfrequency, step sizes, etc. of the profiles 1306, 1308, and 1310 maydepend on which stimulation parameter is being increased according tothe profile. For example, for the medium aggressiveness profile 1306where a final stimulation with a current amplitude of 3.5 mA, afrequency of 20 Hz, and a pulse width of 500 μs is desired, the profile1306 may include steps of 0.125 mA increments for current amplitude, 0.2Hz for frequency, and 30 μs for pulse width. If the profiles 1306, 1308,and 1310 are step functions, at each step the increase amount and typeof the stimulation increase is determined by the trajectory of theprofile 1306, 1308, and 1310. As an example, at each step, amplitude,pulse width, and frequency may all increase, only one or two parametersmay increase, or none of the parameters may increase depending on thetrajectory of the profile 1306, 1308, and 1310 according to which thestimulation is being delivered. Together, the steps for each of thestimulation parameters create a titration curve with a smooth increasein intensity.

In various embodiments, the profiles 1306, 1308, and 1310 have the sameshape and only differ on the scale of the titration. For example, theprofiles 1306, 1308, and 1310 are each stepwise functions using the samesizes of steps. The profiles 1306, 1308, and 1310 instead differ basedon how much time is allowed to pass between moving to the next step.

Accordingly, the steps of the high aggressiveness profile 1308 arecloser together (e.g. more compressed) than the medium aggressivenessprofile 1306, which in turn has steps that are closer together than thelow aggressiveness profile 1310. However, in other embodiments, theprofiles 1306, 1308, and 1310 may instead have differently sized and/orspaced steps, the profiles 1306, 1308, and 1310 may have differentshapes, and so on. Additionally, in certain embodiments, the profiles1306, 1308, and 1310 may implement the same titration for a certainperiod of time (e.g., a standardized portion of the titration) and thenbranch out into their different, respective titration aggressivenessfunctions, for example, after a certain stimulation intensity thresholdis reached.

For VNS systems 11 implementing different titration aggressivenessprofiles, such as shown in graph 1300, the physician inputs the finalstimulation parameters that the titration is designed to reach, and thedefault titration profile for reaching those parameters is the mediumaggressiveness profile 1306. The medium aggressiveness profile 1306 maybe the factory-adjustable default for the VNS system 11, or the mediumaggressiveness profile 1306 may be the recommended profile for thephysician to select (e.g, via the programmer 40) for the titration. Thephysician may then be able to customize the stimulation for the patient.For example, the physician may modify the duty cycle from the default(e.g., 14 seconds ON, 66 seconds OFF, with an amplitude ramp up at thebeginning of each cycle and an amplitude ramp down at the end of eachcycle), after which the duty cycle will be constant during the titrationunless modified again by the physician.

Once the VNS system 11 is thus initialized, stimulation will occuraccording to the medium aggressiveness profile 1306. However, if thepatient experiences unwanted side effects as the titration progresses,the patient can provide a feedback signal indicating that the patient isexperiencing unwanted side effects to the VNS system 11, for example,via the patient magnet 730. Those of skill in the art will appreciate,however, that while reference is made herein to the patient magnet 730,the patient may be able to signal unwanted side effects to the VNSsystem 11 through another mechanism, such as by an external patientprogrammer. Once the patient signals to the VNS system 11 that thepatient is experiencing unwanted side effects, the VNS system 11modifies the titration accordingly. The VNS system 11 may also transmit,via an implantable pulse generator (e.g., the neurostimulator 12), areceipt of the feedback signal to an external device.

In one embodiment, if the patient places the patient magnet 730 over theimplanted system 700 for at least 10 seconds but less than 60 seconds,the implanted system 700 automatically decrements the stimulationintensity along the profile 1306, 1308, or 1310 being used for thepatient. If the titration is decremented three times, the implantedsystem 700 automatically switches the patient to a less aggressivetitration profile, if possible. For example, the implanted system 700switches the patient from the high aggressiveness profile 1308 to themedium aggressiveness profile 1306 or switches the patient from themedium aggressiveness profile 1306 to the low aggressiveness profile1310. In switching to a less aggressive titration profile, the implantedsystem 700 identifies and moves to a location on the less aggressivetitration profile that has a stimulation intensity less than or equal tothe stimulation intensity currently being used on the current profile.As an example, the implanted system 700 moves to the highest location onthe less aggressive titration profile that has a amplitude, frequency,and pulse width less than or equal to the amplitude, frequency, andpulse width currently being applied to the patient according to the moreaggressive titration profile. Alternatively, if the patient places thepatient magnet 730 over the implanted system 700 for at least 60seconds, the implanted system 700 inhibits stimulation until the patientmagnet 730 is removed. Once the patient magnet 730 is removed,stimulation resumes, and the stimulation intensity is not decremented.In some arrangements, if the patient uses the patient magnet 730 todecrement the stimulation intensity, move to a less aggressive profile,and/or pause the stimulation, the implanted system 700 keeps a record ofthe magnet activation. Additionally, the dashboard 800 may factor themagnet activation record into the determination of patient priority 810.

Alternatively, in another embodiment, the patient informs the physicianthat the patient has experienced unwanted side effects, and thephysician can switch the patient to a less aggressive titration profilein response to the patient feedback. Alternatively, if the patient isexperiencing no side effects, the physician can switch the patient to amore aggressive profile (e.g., from the low aggressiveness profile 1310to the medium aggressiveness profile 1306 or from the mediumaggressiveness profile 1306 to the high aggressiveness profile 1308).The physician may be able to switch the profiles in person and/orremotely.

In some arrangements, once the patient is switched from a higheraggressiveness profile to a lower aggressiveness profile, the patientcannot be switched back to the higher aggressiveness profile.Conversely, in other arrangements, the patient may be switched back to ahigher aggressiveness profile (e.g., either automatically by the VNSsystem 11 or by the physician using the programmer 40) if the patientexperiences no further subsequent side effects. Additionally, in variousembodiments, the VNS system 11 keeps a record of the timing of allstimulation parameter changes throughout the titration period. The logincludes a record of, e.g., the timing and duration of all magnet 730activations and can be downloaded from the implanted system 700 forviewing by the physician.

Additionally, those of skill in the art will appreciate that graph 1300is merely exemplary of different aggressiveness profiles. A VNS system11 may implement additional or fewer aggressiveness profiles. Forexample, a VNS system 11 may be adapted to implement a titrationaggressiveness profile that is even less aggressive than the lowaggressiveness profile 1310. Thus, after being moved from the mediumaggressiveness profile 1306 to the low aggressiveness profile 1310, apatient may indicate to the VNS system 11 (e.g., via the patient magnet730) that the patient is still experiencing adverse side effects withthe low aggressiveness profile 1310. Accordingly, the VNS system 11 maymodify the neurostimulation signal to conform to the even lessaggressive titration profile, deliver the modified neurostimulationsignal, and titrate (e.g., gradually increase) the neurostimulationaccording to the even less aggressive titration profile.

FIG. 14 is a flowchart of a titration process 1400 (e.g., implemented bythe VNS system 11) including different titration aggressivenessprofiles, according to an exemplary embodiment. First, the VNS system 11delivers a neurostimulation signal in conformance with a first titrationaggressiveness profile at 1402. For example, the first titrationaggressiveness profile may be the medium aggressiveness profile 1306shown in FIG. 13. Next, the VNS system 11 increases at least oneparameter of the first titration aggressiveness profile (e.g., outputcurrent, frequency, pulse width, or duty cycle) towards a target value(e.g., the target value 1312) at 1404. The VNS system 11 then receives afeedback signal from the patient indicating adverse effects from theneurostimulation signal at 1406. The patient may provide the feedbacksignal to the VNS system 11 via a patient magnet, as described above, orthrough any other feedback mechanism, such as by an external patientprogrammer. In response to the feedback signal, the VNS system 11modifies the neurostimulation signal to conform with a second titrationaggressiveness profile at 1408. For example, as discussed above, the VNSsystem 11 may modify the neurostimulation signal to match the lowaggressiveness profile 1310 shown in FIG. 13. The VNS system 11 deliversthe neurostimulation signal with the second titration aggressivenessprofile at 1410. The VNS system 11 then increases at least one parameterof the second titration aggressiveness profile towards the target valueat 1412.

As described above, stimulation may be applied by the VNS system 11according to a duty cycle, where the duty cycle includes an ON period,an OFF period, an amplitude ramp up at the beginning of each cycle, andan amplitude ramp down at the end of each cycle. Accordingly, in manysituations, it would be beneficial for the physician in a clinic settingto be able to determine when therapy is actually being applied by theVNS system 11. As such, referring back to FIG. 3, in addition toallowing the physician to interrogate the neurostimulator 12 and setparameters, the external programmer 40 may display indicate to the userwhether the VNS system 11 is currently delivering therapy to the patient(e.g., the “therapy active” status) based on interrogation of theneurostimulator 12. In various embodiments, the external programmer 40may display the therapy active status on the visual display 44 of theprogramming computer 41. For example, in one embodiment, the visualdisplay 44 may include an on-off therapy status indicator and show viathe indicator whether the neurostimulator 12 is ON or OFF. In anotherembodiment, in response to an interrogation of the neurostimulator 12,the external programmer 40 may display a countdown time to the nextstimulation burst.

The external programmer 40 may display the therapy active status in realtime. Alternatively, the external programmer 40 may display the therapyactive status asynchronously from the interrogation response from theneurostimulator 12 such that the external programmer 40 accounts for thetransport delay between the external programmer 40 and theneurostimulator 12 and the display of the therapy active statuscoincides with the stimulation burst being applied to the patient. Inanother arrangement, when interrogating the neurostimulator 12, theexternal programmer 40 may query the neurostimulator 12 to receive ablock of timing data that enables the programmer 40 to sync its therapyactive displays to the stimulation delivered by the VNS system 11.Additionally, in yet another arrangement, the external programmer 40 maydisplay the therapy active status in real time or accounting for thetransport delay while in communication with the neurostimulator 12 andalso receive a block of timing data that enables the programmer 40 tocontinue displaying the therapy active status once communication ceasesbetween the external programmer 40 and the neurostimulator 12.

FIG. 15 is a flowchart of a process 1500 (e.g., implemented by theprogrammer 40) of displaying an indication of active neurostimulation,according to an exemplary embodiment. The external programmer 40 firstcommunicates with an implantable pulse generator (e.g., theneurostimulator 12) to collect data about ongoing neurostimulationapplied by the neurostimulator 12 at 1502. For example, as discussedabove, the external programmer 40 interrogates the neurostimulator 12and receives back information on whether the neurostimulator 12 iscurrently providing active stimulation, information relating to thetiming to the next active stimulation, information relating to thetiming of future stimulation bursts, and so on. The external programmer40 then displays (e.g., via the visual display 44) an indicationrelating to a timing of neurostimulation bursts applied by theneurostimulator 12 at 1504. As an example, the external programmer 40may display a therapy active status such as an on-off therapy statusindicator, a countdown time to the next stimulation burst, and so on.Additionally, the external programmer 40 may display the therapy activestatus in real time, based on a transport delay between the externalprogrammer 40 and the neurostimulator 12 such that the display coincideswith the stimulation burst actually being applied, based on a block oftiming data from the neurostimulator 12, and so on.

As yet another example of titration configured to reduce adverse sideeffects in the patient, FIG. 16 is a patient titration graph 1600incorporating a titration black-out period, according to an exemplaryembodiment. The graph 1600 includes an x-axis 1602 and a y-axis 1604.The x-axis 1602 is a unit of time (e.g., days, weeks, months, etc.),while the y-axis 1604 is a parameter of stimulation (e.g., amplitude,frequency, pulse width, duty cycle, etc.). In various embodiments, thetitration graph 1600 may be incorporated in a user interface displayedto a physician (e.g., on the external programmer 40 or other computingdevice) during the titration configuration process.

As shown in the graph 1600, titration may be accomplished as a stepfunction (e.g., with multiple small stimulation intensity increase stepsimplemented per day, such as four times a day) incorporating one or moreblack-out periods 1606, shown in graph 1600 as the hold period between astart hold time 1608 and a stop hold time 1610. During the black-outperiod 1606, stimulation is kept constant, and no titration steps occur.Black-out periods 1606 may be implemented on titration to help ensurethat the patient does not observe adverse side effects and therebyexperience discomfort during the titration. For example, black-outperiods 1606 may be implemented during a time of day or a duration oftime during which the patient is more likely to experience side effectsof the titration. Accordingly, in some embodiments, black-out periods1606 may be implemented during the night because the increasedstimulation intensity as a result of increased titration steps causesthe patient to awaken. Conversely, in other embodiments, black-outperiods 1606 may be implemented during the daytime, as the patient isless likely to notice an adverse side effect from the titration when thepatient is sleeping.

Black-out periods 1606 may be programmed into a patient's titrationschedule through various methods. In one embodiment, the timing andduration of black-out periods 1606 are preset as part of the firmwaredesign (e.g., programmed to occur from 10 pm to 8 am, during when mostindividuals sleep). In another embodiment, the timing and duration ofblack-out periods 1606 are programmable by technicians for the VNSsystem 11. In a third embodiment, a physician can program a presettiming and duration of black-out periods 1606 (e.g., by using theprogrammer 40) based on the patient's schedule (e.g., program black-outperiods 1606 during time periods when the patient is usually awake orusually asleep). In a fourth embodiment, the patient can program apreset timing and duration of black-out periods 1606 (e.g., by using theexternal programmer 707). In a fifth embodiment, the patient can use auser device (e.g., a handheld unit, the patient magnet 730, etc.) toindicate to the VNS device 11 when the patient is going to bed and whenthe patient has woken up, and the VNS device begins or suspendsblack-out periods 1606 accordingly. Alternatively, the patient can usethe user device to delay a default black-out period 1606 or start adefault black-out period 1606 early.

FIG. 17 is a flowchart of a titration process 1700 (e.g., implemented bythe VNS system 11) incorporating a titration black-out period (e.g., theblack-out period 1606), according to an exemplary embodiment. The VNSsystem 11 first delivers a neurostimulation signal at 1702. Theneurostimulation signal is delivered in conformance with a set ofparameters (e.g., output current, frequency, pulse width, duty cycle,etc.). The VNS system 11 begins titrating the neurostimulation signal at1704. For example, the VNS system 11 increases (e.g., graduallyincreases) at least one stimulation parameter of the neurostimulationsignal according to a stepwise function. The VNS system 11 then receivesa first indicator associated with a titration hold time and/or atitration hold duration (e.g., the start hold 1606 instruction shown inFIG. 16) at 1706. As discussed above, the first indicator may be apreset black-out start hold time 1608 (e.g., fixed as part of thefirmware design or programmed by a technician, a physician, or thepatient) or may be an indicator sent by a user device to the VNS system11 (e.g., indicating that the patient is planning on going to bed orthat the patient has awoken).

In response, the VNS system 11 holds titration of the neurostimulationsignal by continuing the neurostimulation signal at the signalparameters being delivered at the time the first indicator was receivedat 1708. Subsequently, the VNS system 11 receives a second indicatorassociated with a titration resumption time and/or the completion of thetitration hold time (e.g., the stop hold time 1610) at 1710. Forexample, as discussed above, the second indicator may be the expirationof the preprogrammed black-out period or may be an indicator sent by theuser device to the VNS system 11 (e.g., indicating that the patient hasawoken or that the patient is planning on going to bed). In response tothe second indicator, the VNS system 11 resumes titrating theneurostimulation signal at 1712. Additionally, while FIG. 16 illustratesa resumption of the titration after the black-out period 1606 occurringat the same level as before the black-out period 1606, in someembodiments, the VNS system 11 may increase the neurostimulation afterthe black-out period 1606 and/or modify the rate of the titration afterthe black-out period 1606. As such, through the titration process 1700,a temporary titration hold may be applied to the neurostimulationprovided to the patient to reduce adverse effects observed by thepatient during the titrating.

In various embodiments, the VNS system 11 may also be configured toprovide “titration training” to the patient under the supervision of aphysician. The goal of the titration training is to provide increasingstimulation intensity to the patient at a controlled rate over arelatively short period of time (e.g., 10 minutes) so that the patientcan experience the sensation of stimulation. For example, at thebeginning of the titration period for a patient, the physician interactswith the patient in a titration training session. During the session,the VNS system 11 provides stimulation levels that are (1)imperceptible, (2) perceptible but tolerable, and/or (3) perceptible andslightly intolerable to the patient (e.g., in response to an indicationfrom the physician via the external programmer 40 to conduct titrationtraining). By educating the patient, and well as the patient's caregiverin certain arrangements, through the titration training session on theexpected levels of stimulation during the titration period, patients maybecome acclimated to the sensation of mild stimulation in the midst ofrapid accommodation to stimulation. In this way, the training mayimprove the timeliness and sensitivity of magnet interventions from thepatient in response to the titration (e.g., by teaching the patient whatside effects feel like so that the patient only uses the magnetinterventions when a side effect is actually present). As such, thesetraining sessions may help the titration and patient accommodationprocesses to proceed smoothly without unnecessary interruptions. Thesesessions may also allow the physician to assess the patient and/orcaregiver motivation, cognitive ability, and physical abilities beforethe physician activates the titration.

While embodiments been particularly shown and described, those skilledin the art will understand that the foregoing and other changes in formand detail may be made therein without departing from the spirit andscope. For example, in various embodiments described above, thestimulation is applied to the vagus nerve. Alternatively, spinal cordstimulation (SCS) may be used in place of or in addition to vagus nervestimulation for the above-described therapies. SCS may utilizestimulating electrodes implanted in the epidural space, an electricalpulse generator implanted in the lower abdominal area or gluteal region,and conducting wires coupling the stimulating electrodes to thegenerator.

The present disclosure contemplates methods, systems, and programproducts on any machine-readable media for accomplishing variousoperations. The embodiments of the present disclosure may be implementedusing existing computer processors, or by a special purpose computerprocessor for an appropriate system, incorporated for this or anotherpurpose, or by a hardwired system. Embodiments within the scope of thepresent disclosure include program products comprising machine-readablemedia for carrying or having machine-executable instructions or datastructures stored thereon. Such machine-readable media can be anyavailable media that can be accessed by a general purpose or specialpurpose computer or other machine with a processor. By way of example,such machine-readable media can comprise RAM, ROM, EPROM, EEPROM, CD-ROMor other optical disk storage, magnetic disk storage or other magneticstorage devices, or any other medium which can be used to carry or storedesired program code in the form of machine-executable instructions ordata structures and which can be accessed by a general purpose orspecial purpose computer or other machine with a processor. Wheninformation is transferred or provided over a network or anothercommunications connection (either hardwired, wireless, or a combinationof hardwired or wireless) to a machine, the machine properly views theconnection as a machine-readable medium. Thus, any such connection isproperly termed a machine-readable medium. Combinations of the above arealso included within the scope of machine-readable media.Machine-executable instructions include, for example, instructions anddata which cause a general purpose computer, special purpose computer,or special purpose processing machines to perform a certain function orgroup of functions.

Although the figures may show a specific order of method steps, theorder of the steps may differ from what is depicted. Also two or moresteps may be performed concurrently or with partial concurrence. Suchvariation will depend on the software and hardware systems chosen and ondesigner choice. All such variations are within the scope of thedisclosure. Likewise, software implementations could be accomplishedwith standard programming techniques with rule based logic and otherlogic to accomplish the various connection steps, processing steps,comparison steps and decision steps.

Also, the term “or” is used in its inclusive sense (and not in itsexclusive sense) so that when used, for example, to connect a list ofelements, the term “or” means one, some, or all of the elements in thelist. Conjunctive language such as the phrase “at least one of X, Y, andZ,” unless specifically stated otherwise, is otherwise understood withthe context as used in general to convey that an item, term, etc. may beeither X, Y, Z, X and Y, X and Z, Y and Z, or X, Y, and Z. Thus, suchconjunctive language is not generally intended to imply that certainembodiments require at least one of X, at least one of Y, and at leastone of Z to each be present.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopeand spirit being indicated by the following claims.

What is claimed is:
 1. A method of titrating a neurostimulation signaldelivered to a patient from an implantable pulse generator, the methodcomprising: delivering a first neurostimulation signal with a first setof parameters, the first set of parameters having a first value for atleast one of output current, frequency, pulse width, or duty cycle;increasing the first value of the first neurostimulation signal at afirst rate for a first period of time while delivering the firstneurostimulation signal; ceasing delivery of the first neurostimulationsignal when the first value reaches a first target value; delivering asecond neurostimulation signal with a second set of parameters, thesecond set of parameters having a second value for at least one ofoutput current, frequency, pulse width, or duty cycle, the second valuebeing equal to the first target value; and increasing the secondneurostimulation signal at a second rate for a second period of timewhile delivering the second neurostimulation signal, the second ratebeing different than the first rate.
 2. The method of claim 1, whereinthe first target value comprises an output current of approximately 0.75mA.
 3. The method of claim 1, further comprising: ceasing delivery ofthe second neurostimulation signal when the second value reaches asecond target value; delivering a third neurostimulation signal with athird set of parameters, the third set of parameters having a thirdvalue for at least one of output current, frequency, pulse width, orduty cycle, the third value being equal to the second target value; andincreasing the third neurostimulation signal at a third rate for a thirdperiod of time while delivering the third neurostimulation signal. 4.The method of claim 3, wherein the third rate is equal to the firstrate.
 5. The method of claim 3, wherein the second target valuecomprises an output current of approximately 1.0 mA.
 6. The method ofclaim 1, wherein the second period of time is greater than the firstperiod of time.
 7. The method of claim 6, wherein the second period oftime is between 1 day and 7 days.
 8. A method of titrating aneurostimulation signal delivered to a patient from an implantable pulsegenerator, the method comprising: delivering the neurostimulation signalin conformance with a first titration aggressiveness profile, the firsttitration aggressiveness profile having a first set of parameters havinga first value for at least one of output current, frequency, pulsewidth, or duty cycle; increasing the first value for the at least one ofoutput current, frequency, pulse width, or duty cycle towards a targetvalue; receiving a feedback signal from the patient indicating adverseeffects from the neurostimulation signal; and in response to receivingthe feedback signal: modifying the neurostimulation signal to conformwith a second titration aggressiveness profile, the secondaggressiveness profile having a second set of parameters having a secondvalue for at least one of output current, frequency, pulse width, orduty cycle; delivering the neurostimulation signal with the secondtitration aggressiveness profile; and increasing the second value forthe at least one of output current, frequency, pulse width, or dutycycle towards the target value.
 9. The method of claim 8, wherein thesecond titration aggressiveness profile corresponds to a less aggressivetitration and the first titration aggressiveness profile corresponds toa more aggressive titration, the more aggressive titration defined by atleast one of the following as compared to the less aggressive titration:a shorter time interval associated with a transition from the first setof parameters to the target value, a greater target intensity, or agreater increment value between the first value and the target value.10. The method of claim 8, further comprising: receiving a secondfeedback signal from the patient indicating adverse effects from theneurostimulation signal; modifying the neurostimulation signal toconform with a third titration aggressiveness profile, the thirdaggressiveness profile having a third set of parameters having a thirdvalue for at least one of output current, frequency, pulse width, orduty cycle; delivering the neurostimulation signal with the thirdtitration aggressiveness profile; and increasing the third value for theat least one of output current, frequency, pulse width, or duty cycletowards the target value.
 11. The method of claim 10, wherein the thirdtitration aggressiveness profile corresponds to a less aggressivetitration and the second titration aggressiveness profile corresponds toa more aggressive titration, the more aggressive titration defined by atleast one of the following as compared to the less aggressive titration:a shorter time interval associated with a transition from the first setof parameters to the target value, a greater target intensity, or agreater increment value between the first value and the target value.12. The method of claim 8, wherein modifying the neurostimulation signaloccurs after receiving the feedback signal a plurality of times.
 13. Themethod of claim 8, wherein receiving the feedback signal comprisesdetecting the feedback signal using a magnet detection circuitconfigured to detect a presence of a magnet in proximity of theimplantable pulse generator.
 14. The method of claim 8, furthercomprising transmitting, via the implantable pulse generator, receipt ofthe feedback signal to an external device.
 15. A programmer configuredto communicate with an implantable pulse generator that providesneurostimulation, the programmer comprising: communication circuitry; auser interface; a processor; and a memory having instructions storedthereon that, when executed by the processor, cause the processor to:collect, via the communication circuitry, data from the implantablepulse generator about ongoing neurostimulation being applied by theimplantable pulse generator while in communication with thecommunication circuitry; and display, via the user interface, anindication relating to a timing of neurostimulation bursts applied bythe implantable pulse generator while in communication with thecommunication circuitry based on the collected data.
 16. The programmerof claim 15, wherein the indication comprises a countdown time until asubsequent neurostimulation burst.
 17. The programmer of claim 15,wherein the indication comprises at least one of a therapy on indicationor a therapy off indication.
 18. The programmer of claim 15, wherein theinstructions cause the processor to display the indication in real time.19. The programmer of claim 15, wherein the instructions cause theprocessor to display the indication according to a time delay thataccounts for a transport delay between the implantable pulse generatorand the programmer such that the indication displayed coincides with anactual application of each stimulation burst by the implantable pulsegenerator.
 20. The programmer of claim 15, wherein the collected dataincludes timing data for future neurostimulation bursts to be applied bythe implantable pulse generator, and wherein the instructions furthercause the processor to synchronously display, via the user interface, anindication relating to a timing of the future neurostimulation bursts asthe future neurostimulation bursts are applied by the implantable pulsegenerator.
 21. A method of titrating a neurostimulation signal deliveredto a patient from an implantable pulse generator, the method comprising:delivering the neurostimulation signal in conformance with a first setof parameters, the first set of parameters having a first value for atleast one of output current, frequency, pulse width, or duty cycle;receiving a first indicator associated with at least one of a titrationhold time or a titration hold duration; initiating a titration hold ofthe titrating of the neurostimulation signal in response to the firstindicator, the titration hold corresponding to a continuation of theneurostimulation signal conforming with the first set of parameters;receiving a second indicator, the second indicator associated with atleast one of a titration resumption time or a completion of thetitration hold duration; and resuming the titrating of theneurostimulation signal in response to the second indicator; wherein thetitration hold is a temporary hold configured to reduce adverse effectsobserved by the patient during the titrating.
 22. The method of claim21, wherein resuming the titrating of the neurostimulation signalcomprises, subsequent to receipt of the second indicator, delivering theneurostimulation signal in conformance with a second set of parameters,the second set of parameters having a second value for at least one ofoutput current, frequency, pulse width or duty cycle, the second valuebeing greater than the first value.
 23. The method of claim 21, whereinthe titration hold time corresponds to a time of day in which thepatient is more likely to experience side effects of titrating.
 24. Themethod of claim 21, wherein the titration hold duration corresponds to aduration of time in which the patient is more likely to experience sideeffects of titrating.
 25. The method of claim 21, wherein at least oneof the first indicator or the second indicator is received from a userdevice.
 26. The method of claim 25, wherein the user device is a magnet.27. The method of claim 21, wherein the at least one of the titrationhold time or the titration hold duration are preset.